Fused ring compound and use thereof

ABSTRACT

Provided is a novel compound represented by the following formula 
                         
Wherein each symbol is as defined in the specification, or a salt thereof, which has an angiotensin II receptor antagonistic activity and a peroxisome proliferator-activated receptor γ agonistic activity, and is useful as an agent for the prophylaxis or treatment of circulatory diseases such as hypertension and the like and/or metabolic diseases such as diabetes and the like, and the like.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a novel fused ring compound havingsuperior properties as a medicament, a production method thereof and usethereof. More particularly, the present invention relates to a fusedheterocyclic compound having a particular structure, a superiorpharmacological activity such as angiotensin II receptor antagonisticactivity, peroxisome proliferator-activated receptor γ agonisticactivity and the like, and superior properties such as crystallinity,stability and the like, which is useful as an agent for the prophylaxisor treatment of circulatory diseases such as hypertension, cardiacdiseases (cardiac hypertrophy, cardiac failure, myocardial infarctionetc.), arteriosclerosis, renal diseases (diabetic nephropathy, chronicglomerulonephritis etc.), ophthalmic diseases, liver diseases, cerebralapoplexy and the like and/or metabolic diseases such as hyperlipidemia,obesity, diabetes and the like, a salt thereof, a prodrug thereof, aproduction method thereof, and use thereof and the like.

BACKGROUND OF THE INVENTION

Heretofore, compounds having an angiotensin II receptor antagonisticactivity and a peroxisome proliferator-activated receptor γ agonisticactivity have been reported, for example, in WO2008/062905,WO2008/143262 and the like.

WO 2008/062905 describes a compound of the following formula

wherein R1 is (1) an oxo group; (2) a thioxo group; (3) a grouprepresented by the formula: ═N—R; R is(i) an optionally substituted C₁-C₆ alkyl group or the like;a group represented by the formula:

is

wherein R2 is a group represented by the formula:

wherein R6 is a group represented by the formula:

wherein Z is O or S(O)_(n) (n is an integer of 0 to 2), andY is an optionally substituted C₁-C₄ alkylene group or the like;R3 and R4 are each independently(1) a hydrogen,(2) an optionally substituted C₁-C₆ alkyl group or the like,andR5 is(1) a hydrogen,(2) an optionally substituted C₁-C₆ alkyl group,(3) an optionally substituted C₂-C₆ alkenyl group,(4) an optionally substituted cyclic group,(5) a group represented by the formula: —CO—R8wherein R8 is an optionally substituted C₁-C₆ alkyl group or anoptionally substituted cyclic group, or(6) a group represented by the formula: —O—R8′wherein R8′ is an optionally substituted C₁-C₆ alkyl group or anoptionally substituted cyclic group, or a salt thereof.

WO2008/143262 describes a compound represented by the formula (I):

wherein a group represented by the formula:

is a group represented by the formula (a):

wherein,R1 is a hydrogen atom, a (C₁-C₆)alkyl group optionally havingsubstituent(s) or the like;X is a group represented by the formula: CO—X1, S(O)_(n)—X1 or(R2)C═C(R3) wherein X1 is a group represented by the formula: N(R4) or(R5)C(R6) wherein R4 and R5 are each a hydrogen atom, a (C₁-C₆)alkylgroup optionally having substituent(s), or a cyclic group optionallyhaving substituent(s), and R6 is a (C₁-C₆)alkyl group optionally havingsubstituent(s), R2 is a hydrogen atom, a (C₁-C₆)alkyl group optionallyhaving substituent(s) or the like, R3 is a hydrogen atom, a (C₁-C₆)alkylgroup optionally having substituent(s), or a cyclic group optionallyhaving substituent(s), and n is 1 or 2;Y is a nitrogen atom or a group represented by the formula: C(R7)wherein R7 is a hydrogen atom, or a (C₁-C₆)alkyl group optionally havingsubstituent(s); andm is 0 or 1, providedwhen m is 1, R3 or R4 is optionally bonded to a carbon atom, which isadjacent to the nitrogen atom or a carbon atom bonded thereto, to form aring,R is a croup represented by the formula:

wherein,Ra is a (C₁-C₆)alkylene group optionally having substituent(s) or thelike; Rb is a group represented by the formula:

wherein W is an oxygen atom or a sulfur atom, which optionally hassubstituent(s), wherein the biphenyl group optionally further havingsubstituent(s), or a salt thereof and the like.

In addition, US2004/127443 describes a method for treating or preventingan inflammatory or metabolic disorder in a mammal by administering, tothe mammal in need thereof, a therapeutically effective amount of acompound sufficient to (a) at least partially activate peroxisomeproliferator activated receptors (PPARs) and (b) at least partiallyinhibit, antagonize or block an activity of angiotensin II type 1receptors.

WO1995/26724 describes a method of improving insulin resistance using anangiotensin II receptor antagonist and a method of improving insulinsensitivity accompanying a treatment of hypertension.

WO2007/053406, WO2007/051007, WO2007/013078, WO2006/000564,WO2005/288272, WO2005/020984, WO2004/053903, WO1996/40258, WO1996/40257,WO1996/40256, WO1996/40255, WO2009/137465, WO2009/118292, WO2009/039069,US2009/0012052 and WO2008/060899 describe the compound of the followingformula and that the compound has angiotensin II antagonistic activityand hypotensive activity and is useful as therapeutic agents forcirculatory disease such as hypertension, cardiac diseases, cerebralapoplexy and the like.

WO1994/17067 describes compounds represented by the following formulas,and that the compounds have angiotensin II antagonistic activity andhypotensive activity and are useful as therapeutic agents forcirculatory disease such as hypertension, cardiac diseases, cerebralapoplexy and the like.

U.S. Pat. No. 5,389,632 describes a compound represented by thefollowing formula

wherein one of R¹ and R² is C₁₋₆ alkyl, —(CH₂)_(p)OR (p is an integer of1 to 6, and R is C₁₋₆ alkyl or benzyl) and the other of R¹ and R² is ahydrogen atom, a halogen atom, C₁₋₆ alkyl, OR⁴, SR⁴, NR⁵R⁶ orNH(CH₂)_(n)—NR⁵R⁶ (wherein R⁴ is a hydrogen atom, C₁₋₆ alkyl, C₃₋₇cycloalkyl, (CH₂)_(m)—COOR′ or (CH₂)_(m)—O—R′ (wherein m is an integerof 1 to 4, and R′ is a hydrogen atom or C₁₋₆ alkyl), R⁵ and R⁶ are thesame or different and each is a hydrogen atom, C₁₋₆ alkyl or C₃₋₇cycloalkyl, or R⁵ and R⁶ form, together with the nitrogen atom bonded tothe both, a hetero ring selected from morpholine, pyrrolidine andpiperidine, and n is an integer of 1 to 4), X at the 2-position or the3-position of pyrazolo[1,5-a]pyrimidine is a hydrogen atom, C₁₋₆ alkyl,hydroxyl or COOR′ (R′ is as defined above), and R³ is the formula

wherein Z is CH or a nitrogen atom, Z′ is a sulfur atom or an oxygenatom, R¹¹ is a hydrogen atom or a halogen atom, and R¹² is tetrazolyl,CN, COOH or CONH₂,or a salt thereof, and describes that the compound has angiotensin IIantagonistic activity and hypotensive activity, and is useful astherapeutic agent for circulatory diseases such as hypertension, cardiacdiseases, cerebral apoplexy and the like.

U.S. Pat. No. 5,387,747 describes a compound represented by thefollowing formula

wherein one of R¹ and R² is C₁₋₆ alkyl, —(CH₂)_(p)OR or —(CH₂)_(p)OH (pis an integer of 1 to 6, and R is C₁₋₆ alkyl or benzyl) and the other ofR¹ and R² is a hydrogen atom, a halogen atom, C₁₋₆ alkyl, N₃, OR⁴, SR⁴,NR⁵R⁶ or NH(CH₂)_(n)—NR⁵R⁶ (wherein R⁴ is a hydrogen atom, C₁₋₆ alkyl,C₃₋₇ cycloalkyl, (CH₂)_(m)—COOR′ or (CH₂)_(m)—O—R′ (wherein m is aninteger of 1 to 4, and R′ is a hydrogen atom or C₁₋₆ alkyl), R⁵ and R⁶are the same or different and each is a hydrogen atom, C₁₋₆ alkyl orC₃₋₇ cycloalkyl, or R⁵ and R⁶ form, together with the nitrogen atombonded thereto, a hetero ring selected from morpholine, pyrrolidine andpiperidine, and n is an integer of 1 to 4), X and Y are the same ordifferent and when one of them is a nitrogen atom, the other is C—R⁷(wherein R⁷ is a hydrogen atom, C₁₋₆ alkyl, C₂₋₇ cycloalkyl,(CH₂)_(n′)OH (wherein n′ is an integer of 0 to 4), SR′ (R′ is as definedabove), NR⁵R⁶ (R⁵ and R⁶ are the same or different and each is ahydrogen atom, C₁₋₆ alkyl or C₂₋₇ cycloalkyl)), and R³ is the formula

wherein Z is CH or a nitrogen atom, Z′ is a sulfur atom or an oxygenatom, R¹¹ is a hydrogen atom or a halogen atom, and R¹² is tetrazolyl,CN, COOH or CONH₂),or a salt thereof, and describes that the compound has angiotensin IIantagonistic activity and hypotensive activity, and is useful astherapeutic agent for circulatory diseases such as hypertension, cardiacdiseases, cerebral apoplexy and the like.

U.S. Pat. No. 5,231,094 describes a compound represented by the formula

wherein one of R¹ and R² is C₁₋₆ alkyl and the other is a hydrogen atom,a halogen atom, OR⁴, SR⁴, NR⁵R⁶ or NR⁴(CH₂)_(n)—NR⁵R⁶ (wherein R⁴ is ahydrogen atom, C₁₋₆ alkyl or C₃₋₇ cycloalkyl, R⁵ and R⁶ are the same ordifferent and each is a hydrogen atom, C₁₋₆ alkyl or C₃₋₇ cycloalkyl, orR⁵ and R⁶ form, together with the nitrogen atom bonded to the both, ahetero ring selected from morpholine, pyrrolidine, piperazine,piperidine and immidazolidine, and n is an integer of 1 to 4, two of X,Y and Z are nitrogen atoms, and the other is C—R⁷ (wherein R² is ahydrogen atom or C₁₋₆ alkyl), and R³ is tetrazolyl, or a salt thereof,and describes that the compound has angiotensin II antagonistic activityand hypotensive activity, and is useful as a therapeutic agent forcirculatory diseases such as hypertension, cardiac diseases, cerebralapoplexy and the like.

Problems to be Solved by the Invention

An object of the present invention is to provide a novel compoundsuperior as a medicament for the prophylaxis or treatment and the likeof circulatory diseases such as hypertension and the like and/ormetabolic diseases such as diabetes and the like, and the like.

Means of Solving the Problems

The present inventors have conducted intensive studies in an attempt toprovide a new compound showing both superior pharmacological activityand superior physicochemical properties so as to afford a medicamentuseful as an agent for the prophylaxis or treatment of circulatorydiseases such as hypertension and the like and/or metabolic diseasessuch as diabetes and the like and the like, and found that novel fusedring compound represented by the following formula (I) has angiotensinII receptor antagonistic activity and peroxisome proliferator-activatedreceptor (PPAR) γ agonistic activity (including partial agonisticactivity), and is useful as an agent for the prophylaxis or treatment ofcirculatory diseases such as hypertension, cardiac diseases (cardiachypertrophy, cardiac failure, myocardial infarction etc.),arteriosclerosis, renal diseases (diabetic nephropathy, chronicglomerulonephritis etc.), ophthalmic diseases, liver diseases, cerebralapoplexy and the like and/or metabolic diseases such as hyperlipidemia,obesity, diabetes and the like, which resulted in the completion of thepresent invention.

Accordingly, the present invention relates to

[1] a compound represented by the formula (I):

wherein R¹ is a hydrogen atom, an optionally substituted C₁₋₆ alkyl, anoptionally substituted 3- to 10-membered nonaromatic cyclic group or anoptionally substituted 5- or 6-membered aromatic cyclic group,R² is a hydrogen atom, an optionally substituted C₁₋₆ alkyl, anoptionally substituted C₁₋₆ alkoxy, an optionally substituted C₁₋₆alkylthio, an optionally substituted C₁₋₆ alkylsulfinyl or an optionallysubstituted C₁₋₆ alkylsulfonyl,R³ is a hydrogen atom, a halogen atom, an optionally substituted C₁₋₆alkyl or an optionally substituted C₁₋₆ alkoxy,X, Y and Z are each independently a nitrogen atom or CR⁴ wherein R⁴ is ahydrogen atom, a halogen atom, an optionally substituted C₁₋₆ alkyl, anoptionally substituted C₁₋₆ alkoxy or an optionally substituted C₃₋₆cycloalkyl,W is an optionally substituted C₁₋₄ alkylene, —O—W′—, —W′—O—, —N(Ra)—W′—or —W′—N(Ra)— wherein W′ is a bond or an optionally substituted C₁₋₄alkylene, Ra is a hydrogen atom, an optionally substituted C₁₋₆ alkyl oran optionally substituted C₃₋₆ cycloalkyl,A is an optionally substituted 5- or 6-membered divalent aromatic ring,andB is an acyl or an optionally substituted 3- to 10-membered heterocyclicgroup, provided when B is a carboxy, a carbamoyl or a tetrazolyl, R¹ isnot a hydrogen atom, or a salt thereof;[2] the compound of the aforementioned [1], wherein R¹ is an optionallysubstituted C₁₋₆ alkyl, an optionally substituted 3- to 10-memberednonaromatic cyclic group or an optionally substituted 5- or 6-memberedaromatic cyclic group;[3] the compound of the aforementioned [2], wherein X is a nitrogenatom, and Y and Z are each CR⁴ wherein R⁴ is as defined above;[4] the compound of the aforementioned [2], wherein X and Z are nitrogenatoms, and Y is CR⁴ wherein R⁴ is as defined above;[5] the compound of the aforementioned [2], wherein R² is an optionallysubstituted C₁₋₆ alkyl;[6] the compound of the aforementioned [2], wherein R³ is a hydrogenatom;[7] the compound of the aforementioned [2], wherein W is an optionallysubstituted C₁₋₄ alkylene;[8] the compound of the aforementioned [2], wherein A is an optionallysubstituted phenylene, an optionally substituted thiophen-di-yl or anoptionally substituted pyridin-di-yl;[9] the compound of the aforementioned [1], wherein B is a grouprepresented by

wherein i is —O— or —S—, j is —C(═O)—, —C(═S)— or —S(O)_(m)—, and m isan integer of 0, 1 or 2;[10] the compound of the aforementioned [1], which is a compoundrepresented by the formula

whereinR¹ is a C₃₋₈ cycloalkyl optionally substituted by a C₁₋₆ alkoxyoptionally substituted by 1) a halogen atom, 2) a cyano, 3) a hydroxy or4) a C₁₋₆ alkoxy optionally substituted by a halogen atom,R² is a C₁₋₆ alkyl,A is a phenylene optionally substituted by a halogen atom, andR⁴ are each independently a hydrogen atom or a methyl;[11] the compound of the aforementioned [1], which is a compoundrepresented by the formula

whereinR¹ is a C₃₋₈ cycloalkyl optionally substituted by a C₁₋₆ alkoxyoptionally substituted by 1) a halogen atom, 2) a cyano, 3) a hydroxy or4) a C₁₋₆ alkoxy optionally substituted by a halogen atom,R² is a C₁₋₆ alkyl,A is a phenylene optionally substituted by a halogen atom, andR⁴ is a hydrogen atom or a methyl;[12] the compound of the aforementioned [1], which is a compoundrepresented by the formula

whereinR¹ is a cyclohexyl optionally substituted by a C₁₋₆ alkoxy optionallysubstituted by a hydroxy, andR² is a C₁₋₆ alkyl;[13] the compound of the aforementioned [1], which is a compoundrepresented by the formula

whereinR¹ is a cyclohexyl optionally substituted by a C₁₋₆ alkoxy optionallysubstituted by a hydroxy,R² is a C₁₋₆ alkyl, andA is a phenylene optionally substituted by a halogen atom;[14]4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-oneor a salt thereof;[15]6-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-oneor a salt thereof;[16] a prodrug of the compound of the aforementioned [1];[17] a medicament comprising an effective amount of the compound of theaforementioned [1] or a prodrug thereof and a pharmaceuticallyacceptable carrier;[18] the medicament of the aforementioned [17] having an angiotensin IIreceptor antagonistic activity and a peroxisome proliferator-activatedreceptor γ agonistic activity;[19] the medicament of the aforementioned [17] which is an agent for theprophylaxis or treatment of a circulatory disease;[20] the medicament of the aforementioned [17] which is an agent for theprophylaxis or treatment of hypertension, a cardiac disease,arteriosclerosis, a renal disease, an ophthalmic disease, a liverdisease, cerebral apoplexy, hyperlipidemia, obesity, and/or diabetes;[21] a method of inhibiting an angiotensin II receptor and activating aperoxisome proliferator-activated receptor γ in a mammal in needthereof, comprising administering the compound of the aforementioned [1]or a prodrug thereof to the mammal;[22] a method for the prophylaxis or treatment of a circulatory diseasein a mammal in need thereof, comprising administering the compound ofthe aforementioned [1] or a prodrug thereof to the mammal;[23] a method for the prophylaxis or treatment of hypertension, acardiac disease, arteriosclerosis, a renal disease, an ophthalmicdisease, a liver disease, cerebral apoplexy, hyperlipidemia, obesityand/or diabetes in a mammal in need thereof, comprising administeringthe compound of the aforementioned [1] or a prodrug thereof to themammal;[24] the prodrug of the aforementioned [16], which is an ester;[25] the compound of the aforementioned [1], which is an isomer; and thelike.

DETAILED DESCRIPTION OF THE INVENTION

The definition of each symbol of the present specification is describedbelow.

In the present specification, examples of the “halogen atom” include afluorine atom, a chlorine atom, a bromine atom and an iodine atom.

In the present specification, examples of the “C₂₋₆ alkyl” includemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl,—CH₂CH₂C(CH₃)₃, —CH₂CH(CH₂CH₃)₂ and the like.

In the present specification, examples of the “C₂₋₆ alkenyl” includevinyl, allyl, propenyl, isopropenyl, but-3-en-1-yl, pent-4-en-1-yl,hex-5-en-1-yl and the like.

In the present specification, examples of the “C₂₋₆ alkynyl” includeethynyl, prop-2-yn-1-yl, but-3-yn-1-yl, pent-4-yn-1-yl, hex-5-yn-1-yland the like.

In the present specification, examples of the “C₃₋₆ cycloalkyl” includecyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In the present specification, examples of the “C₆₋₁₄ aryl” includephenyl, naphthyl (e.g., 1-naphthyl, 2-naphthyl), anthryl, phenanthryland the like. Preferred is phenyl or naphthyl, and more preferred isphenyl.

In the present specification, examples of the “C₇₋₁₆ aralkyl” includebenzyl, 1-phenylethyl, 2-phenylethyl, naphthylmethyl (1-naphthylmethyl,2-naphthylmethyl), 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl and thelike.

In the present specification, examples of the “C₁₋₆ alkoxy” includemethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy,—OCH(CH₂CH₃)₂, —OCH(CH₃)(CH(CH₃)₂), —OCH₂CH(CH₃)(CH₂CH₃), hexyloxy,—OCH₂CH(CH₂CH₃)₂, —OCH(CH₂CH₃)(CH(CH₃)₂), —OC(CH₃)₂(CH(CH₃)₂) and thelike.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkyl” include the above-mentioned “C₁₋₆ alkyl” optionallysubstituted by 1 to 5 of the above-mentioned “halogen atom”. Forexample, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl,trifluoromethyl and the like can be mentioned.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkoxy” include the above-mentioned “C₁₋₆ alkoxy” optionallysubstituted by 1 to 5 of the above-mentioned “halogen atom”. Forexample, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy,trifluoromethoxy, 2-fluoroethoxy and the like can be mentioned.

In the present specification, examples of the “heterocyclic group”include, unless otherwise specified, a 4- to 14-membered (preferably 5-to 10-membered) (monocyclic, bicyclic or tricyclic) heterocyclic grouphaving, as ring-constituting atom besides carbon atom, 1 to 3 kinds of 1to 4 hetero atoms selected from the group consisting of a nitrogen atom,a sulfur atom and an oxygen atom, preferably (i) 5- to 14-membered(preferably 5- to 10-membered) aromatic heterocyclic group, (ii) 4- to10-membered (preferably 5- to 10-membered) nonaromatic heterocyclicgroup and the like.

Examples of the “aromatic heterocyclic group” include monocyclicaromatic heterocyclic groups such as furyl, thienyl, pyrrolyl, oxazolyl(e.g., 1,3-oxazolyl), isoxazolyl, thiazolyl, isothiazolyl, imidazolyl(e.g., 1H-imidazol-1-yl), pyrazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl (e.g., 1,3,4-oxadiazol-2-yl),furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl (e.g., 1,2,4-triazol-3-yl), tetrazolyl,pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like;aromatic fused heterocyclic groups such as benzofuryl, isobenzofuryl,benzo[b]thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl,benzoxazolyl, benzo[d]isoxazolyl, benzothiazolyl, benzo[d]isothiazolyl,1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl,quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl,carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acrydinyl,phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl,phenathridinyl, phenathridinyl, phenanthrolinyl, indolizinyl,pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl,imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-a]pyridazinyl,imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl,1,2,4-triazolo[4,3-b]pyridazinyl and the like.

Examples of the “nonaromatic heterocyclic group” include monocyclicnonaromatic heterocyclic groups such as azetidinyl, oxetanyl, thietanyl,pyrrolidinyl, tetrahydrofuryl (e.g., tetrahydrofuran-2-yl), thioranyl,imidazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidyl,piperidino, tetrahydropyranyl (e.g., tetrahydropyran-4-yl), morpholinyl,morpholino, thiomorpholinyl, thiomorpholino, piperazinyl,dihydrooxazolyl (e.g., 4,5-dihydro-1,3,4-oxadiazol-2-yl),dihydroisoxazolyl (e.g., 4,5-dihydroisoxazolyl) and the like;nonaromatic fused heterocyclic groups such as isochromanyl,dihydrobenzopyranyl, isochromenyl, chromenyl (2H-chromenyl,4H-chromenyl), 1,2,3,4-tetrahydroisoquinolyl,1,2,3,4-tetrahydroquinolyl, 2,3-dihydrobenzofuranyl, benzo[1,3]dioxolyland the like.

In the present specification, examples of the “5- or 6-memberedheterocyclic group” include, unless otherwise specified, a 5- or6-membered heterocyclic group, for example, 5- or 6-membered monocyclicaromatic heterocyclic groups such as furyl, thienyl, pyrrolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, imidazolyl (e.g.,1H-imidazol-1-yl), pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl (e.g., 1,3,4-oxadiazol-2-yl), furazanyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl (e.g., 1,2,4-triazol-3-yl), tetrazolyl,pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like; 5-or 6-membered monocyclic nonaromatic heterocyclic groups such aspyrrolidinyl, tetrahydrofuryl (e.g., tetrahydrofuran-2-yl), thioranyl,imidazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidyl,piperidino, tetrahydropyranyl (e.g., tetrahydropyran-4-yl), morpholinyl,morpholino, thiomorpholinyl, thiomorpholino, piperazinyl,dihydroisoxazolyl (e.g., 4,5-dihydroisoxazolyl), dihydrooxadiazolyl(e.g., 4,5-dihydro-1,3,4-oxadiazol-2-yl) and the like and the like, fromamong the above-mentioned heterocyclic groups exemplified as the“heterocyclic group”.

In the present specification, examples of the “C₂₋₆ alkenyloxy” includevinyloxy, allyloxy, propenyloxy, isopropenyloxy, but-3-en-1-yloxy,pent-4-en-1-yloxy, hex-5-en-1-yloxy and the like.

In the present specification, examples of the “C₂₋₆ alkynyloxy” includeethynyloxy, prop-2-yn-1-yloxy, but-3-yn-1-yloxy, pent-4-yn-1-yloxy,hex-5-yn-1-yloxy, 1-methylbut-3-yn-1-yloxy and the like.

In the present specification, examples of the “C₃₋₆ cycloalkyloxy”include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy.

In the present specification, examples of the “C₃₋₁₀ cycloalkyloxy”include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy,cycloheptyloxy, cyclooctyloxy and the like.

In the present specification, examples of the “C₆₋₁₄ aryloxy” includephenoxy, 1-naphthyloxy, 2-naphthyloxy and the like.

In the present specification, examples of the “C₇₋₁₆ aralkyloxy” includebenzyloxy, phenethyloxy and the like.

In the present specification, examples of the “C₁₋₆ alkyl-carbonyloxy”include acetyloxy, isopropylcarbonyloxy and the like.

In the present specification, examples of the “5- or 6-memberedheterocyclyl-oxy” include tetrahydrofuryloxy (e.g.,tetrahydrofuran-3-yloxy), tetrahydropyranyloxy (e.g.,tetrahydropyran-4-yloxy), piperidyloxy (e.g., piperidin-4-yloxy),isoxazolyloxy (e.g., isoxazol-3-yloxy) and the like.

In the present specification, examples of the “5- or 6-memberedheterocyclyl-C₁₋₆ alkyloxy” include tetrahydrofurylmethoxy (e.g.,tetrahydrofuran-3-ylmethoxy), tetrahydropyranylmethoxy (e.g.,tetrahydropyran-4-ylmethoxy), piperidylmethoxy (e.g.,piperidin-4-ylmethoxy) and the like.

In the present specification, examples of the “C₁₋₆ alkylamino” includeamino monosubstituted by the above-mentioned “C₁₋₆ alkyl”. For example,methylamino, ethylamino, propylamino, isopropylamino, butylamino,isobutylamino, sec-butylamino, tert-butylamino, pentylamino,isopentylamino, neopentylamino, tert-pentylamino, hexylamino and thelike can be mentioned.

In the present specification, examples of the “di(C₁₋₆)alkylamino”include an amino group disubstituted by the above-mentioned “C₁₋₆alkyl”. For example, dimethylamino, diethylamino, N-ethyl-N-methylaminoand the like can be mentioned.

In the present specification, examples of the “C₁₋₆ alkyl-carbonylamino”include acetylamino, propanoylamino, butanoylamino,2-methylpropanoylamino, pentanoylamino, 3-methylbutanoylamino,2,2-dimethylpropanoylamino and the like.

In the present specification, examples of the “C₁₋₆ alkylthio” includemethylthio, ethylthio, propylthio, isopropylthio, butylthio,sec-butylthio, tert-butylthio and the like.

In the present specification, examples of the “C₁₋₆ alkylsulfinyl”include methylsulfinyl, ethylsulfinyl, propylsulfinyl,isopropylsulfinyl, butylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyland the like.

In the present specification, examples of the “C₁₋₆ alkylsulfonyl”include methylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyland the like.

In the present specification, examples of the “optionally esterifiedcarboxy” include carboxy, C₁₋₆ alkoxy-carbonyl (e.g., methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl etc.), C₆₋₁₄aryloxy-carbonyl (e.g., phenoxycarbonyl etc.), C₇₋₁₆ aralkyloxy-carbonyl(e.g., benzyloxycarbonyl, phenethyloxycarbonyl etc.) and the like.

In the present specification, examples of the “C₁₋₆ alkyl-carbonyl”include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl,3-methylbutanoyl, 2,2-dimethylpropanoyl and the like.

In the present specification, examples of the “C₃₋₁₀cycloalkyl-carbonyl” include cyclopropylcarbonyl, cyclopentylcarbonyl,cyclohexylcarbonyl, adamantylcarbonyl and the like.

In the present specification, examples of the “C₃₋₆ cycloalkyl-carbonyl”include cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl andthe like.

In the present specification, examples of the “C₆₋₁₄ aryl-carbonyl”include benzoyl, 1-naphthoyl, 2-naphthoyl and the like.

In the present specification, examples of the “C₇₋₁₆ aralkyl-carbonyl”include phenylacetyl, 3-phenylpropanoyl and the like.

In the present specification, examples of the “C₁₋₆ alkoxy-carbonyl”include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,tert-butoxycarbonyl and the like.

In the present specification, examples of the “C₆₋₁₄ aryloxy-carbonyl”include phenoxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyland the like.

In the present specification, examples of the “C₇₋₁₆aralkyloxy-carbonyl” include benzyloxycarbonyl, phenethyloxycarbonyl andthe like.

In the present specification, examples of the “5- or 6-memberedheterocyclyl-carbonyl” include 1-pyrrolidylcarbonyl, piperidinocarbonyl,1-piperazinylcarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl,tetrahydropyranylcarbonyl (e.g., tetrahydropyran-4-ylcarbonyl) and thelike.

In the present specification, examples of the “C₁₋₆ alkyl-carbamoyl”include carbamoyl monosubstituted by the above-mentioned “C₁₋₆ alkyl”.For example, methylcarbamoyl, ethylcarbamoyl and the like can bementioned.

In the present specification, examples of the “di(C₁₋₆)alkyl-carbamoyl”include carbamoyl disubstituted by the above-mentioned “C₁₋₆ alkyl”. Forexample, dimethylcarbamoyl, diethylcarbamoyl, N-ethyl-N-methylcarbamoyland the like can be mentioned.

In the present specification, examples of the “C₆₋₁₄ aryl-carbamoyl”include carbamoyl monosubstituted by the above-mentioned “C₆₋₁₄ aryl”.For example, phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyland the like can be mentioned.

In the present specification, examples of the “di(C₆₋₁₄)aryl-carbamoyl”include carbamoyl disubstituted by the above-mentioned “C₆₋₁₄ aryl”. Forexample, diphenylcarbamoyl, dinaphthylcarbamoyl and the like can bementioned.

In the present specification, examples of the “C₁₋₆ alkylsulfamoyl”include sulfamoyl monosubstituted by the above-mentioned “C₁₋₆ alkyl”.For example, methylsulfamoyl, ethylsulfamoyl and the like can bementioned.

In the present specification, examples of the “di(C₁₋₆)alkylsulfamoyl”include sulfamoyl disubstituted by the above-mentioned “C₁₋₆ alkyl”. Forexample, dimethylsulfamoyl, diethylsulfamoyl, N-ethyl-N-methylsulfamoyland the like can be mentioned.

In the present specification, examples of the “C₆₋₁₄ arylsulfamoyl”include sulfamoyl monosubstituted by the above-mentioned “C₆₋₁₄ aryl”.For example, phenylsulfamoyl, 1-naphthylsulfamoyl, 2-naphthylsulfamoyland the like can be mentioned.

In the present specification, examples of the “di(C₆₋₁₄)arylsulfamoyl”include a sulfamoyl group disubstituted by the above-mentioned “C₆₋₁₄aryl”. For example, diphenylsulfamoyl, dinaphthylsulfamoyl and the likecan be mentioned.

In the present specification, examples of the “C₁₋₆ alkoxyimino” includemethoxyimino, ethoxyimino, propoxyimino, isopropoxyimino, butoxyimino,isobutoxyimino, sec-butoxyimino, tert-butoxyimino, pentyloxyimino,hexyloxyimino and the like.

In the present specification, examples of the “hydroxy-C₁₋₆ alkyl”include hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl,1-hydroxy-1-methylethyl and the like.

In the present specification, examples of the “C₁₋₆ alkoxy-C₁₋₆ alkyl”include methoxymethyl, 2-methoxyethyl, 1-methoxyethyl, ethoxymethyl,2-ethoxyethyl and the like.

In the present specification, examples of the substituent of the“optionally substituted C₁₋₆ alkyl”, “optionally substituted C₂₋₆alkenyl”, “optionally substituted C₂₋₆ alkynyl”, “optionally substitutedC₁₋₆ alkoxy” and “optionally substituted C₁₋₆ alkylthio” include 1 to 5,preferably 1 to 3, substituents, selected from the group consisting of

(1) a halogen atom,

(2) hydroxy,

(3) amino,

(4) nitro,

(5) cyano,

(6) optionally halogenated C₁₋₆ alkoxy,

(7) C₃₋₆ cycloalkyloxy,

(8) C₆₋₁₄ aryloxy,

(9) C₇₋₁₆ aralkyloxy,

(10) amino optionally substituted by 1 or 2 substituents selected from

(a) C₁₋₆ alkyl,

(b) C₆₋₁₄ aryl,

(c) C₇₋₁₆ aralkyl, and

(d) C₁₋₆ alkyl-carbonyl,

(11) C₁₋₆ alkylthio,

(12) C₁₋₆ alkylsulfinyl,

(13) C₁₋₆ alkylsulfonyl,

(14) optionally esterified carboxy,

(15) C₁₋₆ alkyl-carbonyl optionally substituted by 1 to 3 halogen atoms,

(16) C₃₋₁₀ cycloalkyl-carbonyl,

(17) C₆₋₁₄ aryl-carbonyl optionally substituted by 1 to 3 halogen atoms,

(18) C₇₋₁₆ aralkyl-carbonyl,

(19) 5- or 6-membered heterocyclyl-carbonyl (e.g., 1-pyrrolidylcarbonyl,piperidinocarbonyl, 1-piperazinylcarbonyl, morpholinocarbonyl,thiomorpholinocarbonyl, tetrahydropyranylcarbonyl (e.g.,tetrahydropyran-4-ylcarbonyl) etc.),

(20) carbamoyl,

(21) thiocarbamoyl,

(22) C₁₋₆ alkyl-carbamoyl,

(23) di(C₁₋₆) alkyl-carbamoyl,

(24) C₆₋₁₄ aryl-carbamoyl,

(25) di(C₆₋₁₄)aryl-carbamoyl,

(26) sulfamoyl,

(27) C₁₋₆ alkylsulfamoyl,

(28) di(C₁₋₆) alkylsulfamoyl,

(29) C₆₋₁₄ arylsulfamoyl,

(30) di(C₆₋₁₄)arylsulfamoyl,

(31) a 3- to 14-membered cyclic group (preferably, cyclopropyl,cyclohexyl, phenyl, pyridyl, oxetanyl, benzimidazolyl (e.g.,benzimidazol-2-yl)) optionally substituted by 1 to 3 substituentsselected from the group consisting of (a) a halogen atom, (b) C₁₋₆ alkyloptionally substituted by hydroxy, (c) C₆₋₁₄ aryl, (d) C₁₋₆ alkoxy and(e) C₁₋₆ alkyl-carbonyl,(32) C₁₋₆ alkoxyimino, and the like (hereinafter to be sometimesabbreviated as substituent group A). When the number of the substituentsis two or more, the respective substituents may be the same ordifferent.

In the present specification, examples of the “3- to 14-membered cyclicgroup” of the “optionally substituted 3- to 14-membered cyclic group”include a 3- to 14-membered cyclic hydrocarbon group and a 4- to14-membered heterocyclic group.

Examples of the “3- to 14-membered cyclic hydrocarbon group” include analicyclic hydrocarbon group constituted with 3 to 14 carbon atoms, or anaromatic hydrocarbon group constituted with 6 to 14 carbon atoms and thelike.

Examples of the “3- to 14-membered alicyclic hydrocarbon group” includeC₃₋₆ cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyletc.), C₃₋₆ cycloalkenyl (e.g., cyclopentenyl, cyclohexenyl etc.), C₅₋₁₄cycloalkadienyl (e.g., 2,4-cyclopentadienyl, 1,3-cyclohexadienyl etc.),indanyl, adamantyl and the like.

Examples of the “6- to 14-membered aromatic hydrocarbon group” includeC₆₋₁₄ aryl (e.g., phenyl, naphthyl, anthryl, phenanthryl etc.) and thelike.

Examples of the “4- to 14-membered heterocyclic group” include thosesimilar to the aforementioned “heterocyclic group”.

In the present specification, the “3- to 14-membered cyclic group” ofthe “optionally substituted 3- to 14-membered cyclic group” optionallyhas 1 to 5, preferably 1 to 3, substituents at substitutable positions.Examples of such substituent include those similar to the substituentsthat the “3- to 10-membered nonaromatic cyclic group” of the “optionallysubstituted 3- to 10-membered nonaromatic cyclic group” mentioned belowas R¹ and the “5- or 6-membered aromatic cyclic group” of the“optionally substituted 5- or 6-membered aromatic cyclic group”mentioned below as R¹ optionally have. When the number of thesubstituents is two or more, the respective substituents may be the sameor different.

In the present specification, the “C₆₋₁₄ aryl-carbonyl” of the“optionally substituted C₆₋₁₄ aryl-carbonyl” optionally has 1 to 5,preferably 1 to 3, substituents at substitutable positions. Examples ofsuch substituent include a halogen atom, hydroxy, optionally halogenatedC₁₋₆ alkyl, optionally halogenated C₁₋₆ alkoxy, amino, C₁₋₆ alkylamino,di(C₁₋₆)alkylamino, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, carboxy, C₁₋₆alkoxy-carbonyl, C₁₋₆ alkyl-carbonyl and the like. When the number ofthe substituents is two or more, the respective substituents may be thesame or different.

In the present specification, examples of the “C₁₋₃ alkylidene” includemethylene, ethylidene, propylidene, isopropylidene and the like.

Each substituent is explained below.

R¹ is a hydrogen atom, optionally substituted C₁₋₆ alkyl, an optionallysubstituted 3- to 10-membered nonaromatic cyclic group or an optionallysubstituted 5- or 6-membered aromatic cyclic group.

Preferable examples of the “C₁₋₆ alkyl” of the “optionally substitutedC₁₋₆ alkyl” for R¹ include methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, neopentyl, —CH₂CH₂C(CH₃)₃ and the like.

Preferable examples of the substituent of the “C₁₋₆ alkyl” of the“optionally substituted C₁₋₆ alkyl” for the above-mentioned R¹ include 1to 5 substituents (preferably 1 to 3) selected from the group consistingof

(1) a halogen atom,

(2) hydroxy,

(3) optionally halogenated C₁₋₆ alkoxy,

(4) carboxy optionally substituted by C₁₋₆ alkoxy,

(5) C₁₋₆ alkyl-carbonyl optionally substituted by 1 to 3 halogen atoms,

(6) C₃₋₁₀ cycloalkyl-carbonyl,

(7) C₆₋₁₄ aryl-carbonyl optionally substituted by 1 to 3 halogen atoms,

(8) carbamoyl,

(9) a 3- to 14-membered cyclic group (preferably, cyclopropyl,cyclohexyl, phenyl, pyridyl, oxetanyl, benzimidazolyl (e.g.,benzimidazol-2-yl)) optionally substituted by 1 to 3 substituentsselected from the group consisting of (a) a halogen atom, (b) C₁₋₆ alkyloptionally substituted by hydroxy, (c) C₆₋₁₄ aryl, (d) C₁₋₆ alkoxy and(e) C₁₋₆ alkyl-carbonyl, and(10) C₁₋₆ alkoxyimino. When the number of the substituents is two ormore, the respective substituents may be the same or different.

Examples of the “3- to 10-membered nonaromatic cyclic group” of the“optionally substituted 3- to 10-membered nonaromatic cyclic group” forR¹ include a “3- to 10-membered nonaromatic hydrocarbon group” and a “4-to 7-membered nonaromatic heterocyclic group”.

Examples of the “3- to 10-membered nonaromatic hydrocarbon group”include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl,cycloheptyl, cyclooctyl, adamantyl and the like. Preferred arecyclobutyl, cyclohexyl, cyclohexenyl, adamantyl and the like.

Examples of the “4- to 7-membered nonaromatic heterocyclic group”include azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl,thioranyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl,piperidyl (e.g., piperidin-4-yl), tetrahydropyranyl,tetrahydrothiopyranyl, tetrahydroindazolyl (e.g.,4,5,6,7-tetrahydroindazol-5-yl), morpholinyl, thiomorpholinyl,piperazinyl, oxepanyl (e.g., oxepan-4-yl) and the like. Preferred aretetrahydrofuryl, piperidyl (e.g., piperidin-4-yl), tetrahydropyranyl,tetrahydrothiopyranyl, tetrahydroindazolyl (e.g.,4,5,6,7-tetrahydroindazol-5-yl), oxepanyl (e.g., oxepan-4-yl) and thelike.

Examples of the “5- or 6-membered aromatic cyclic group” of the“optionally substituted 5- or 6-membered aromatic cyclic group” for R¹include phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, triazinyl and the like. Preferred are phenyl and thienyl.

The “3- to 10-membered nonaromatic cyclic group” of the “optionallysubstituted 3- to 10-membered nonaromatic cyclic group” for R¹ or the“5- or 6-membered aromatic cyclic group” of the “optionally substituted5- or 6-membered aromatic cyclic group” for R¹ optionally has 1 to 5,preferably 1 to 3, substituents at substitutable positions. Examples ofsuch substituent include

(1) a halogen atom,

(2) oxo,

(3) hydroxy,

(4) amino optionally substituted by 1 or 2 substituents selected from

(a) C₁₋₆ alkyl,

(b) C₆₋₁₄ aryl,

(c) C₇₋₁₆ aralkyl,

(d) C₁₋₆ alkyl-carbonyl, and

(e) a 5- or 6-membered heterocyclic group,

(5) nitro,

(6) cyano,

(7) C₁₋₆ alkyl optionally substituted by 1 to 3 substituents selectedfrom

(a) hydroxy,

(b) a halogen atom,

(c) C₁₋₆ alkoxy,

(d) C₆₋₁₄ aryl, and

(e) a 5- or 6-membered heterocyclic group optionally substituted by 1 to3 substituents selected from the group consisting of C₁₋₆ alkyl, hydroxyand oxo,

(8) C₂₋₆ alkenyl optionally substituted by hydroxy,

(9) C₂₋₆ alkynyl,

(10) C₃₋₆ cycloalkyl,

(11) C₆₋₁₄ aryl optionally substituted by hydroxy,

(12) C₇₋₁₆ aralkyl,

(13) a heterocyclic group optionally substituted by C₁₋₆ alkyl,

(14) C₁₋₆ alkoxy optionally substituted by 1 to 4 substituents selectedfrom

(a) a halogen atom,

(b) hydroxy,

(c) C₃₋₆ cycloalkyl optionally substituted by 1 to 3 substituentsselected from the group consisting of C₁₋₆ alkyl optionally substitutedby hydroxy, hydroxy, oxo, carbamoyl and cyano,

(d) C₂₋₆ alkenyl,

(e) C₁₋₆ alkoxy,

(f) cyano,

(g) C₁₋₆ alkyl-carbonyl optionally substituted by 1 to 3 halogen atoms,

(h) C₃₋₁₀ cycloalkyl-carbonyl,

(i) carbamoyl,

(j) C₁₋₆ alkoxyimino,

(k) C₁₋₆ alkylthio,

(l) C₁₋₆ alkylsulfonyl,

(m) C₁₋₆ alkyl-carbonyloxy,

(n) C₃₋₆ cycloalkyloxy optionally substituted by 1 to 3 substituentsselected from the group consisting of C₁₋₆ alkyl, hydroxy and oxo, and

(o) a 5- or 6-membered heterocyclic group optionally substituted by 1 to3 substituents selected from the group consisting of C₁₋₆ alkyl, hydroxyand oxo,

(15) C₂₋₆ alkenyloxy optionally substituted by hydroxy,

(16) C₂₋₆ alkynyloxy,

(17) C₃₋₁₀ cycloalkyloxy optionally substituted by 1 to 3 substituentsselected from the group consisting of

(a) oxo,

(b) hydroxy,

(c) C₁₋₆ alkyl optionally substituted by hydroxy, and

(d) C₁₋₆ alkoxy-C₁₋₆ alkyl,

(18) C₆₋₁₄ aryloxy optionally substituted by 1 to 3 substituentsselected from

(a) hydroxy,

(b) C₁₋₆ alkyl optionally substituted by hydroxy,

(c) C₁₋₆ alkyl-carbonyl, and

(d) C₁₋₆ alkoxy,

(19) C₇₋₁₆ aralkyloxy,

(20) 5- or 6-membered heterocyclyl-oxy optionally substituted by 1 to 3substituents selected from

(a) hydroxy, and

(b) C₁₋₆ alkyl

(preferably, 5- or 6-membered heterocyclyl-oxy optionally substituted by1 to 3 C₁₋₆ alkyl),

(21) 5- or 6-membered heterocyclyl-C₁₋₆ alkyloxy,

(22) C₁₋₆ alkyl-carbonyloxy optionally substituted by 1 to 3substituents selected from

(a) hydroxy, and

(b) C₁₋₆ alkyl-carbonylox_(Yf)

(23) C₁₋₆ alkylthio,

(24) C₁₋₆ alkylsulfinyl,

(25) C₁₋₆ alkylsulfonyl,

(26) carboxy optionally substituted by C₁₋₆ alkoxy,

(27) C₁₋₆ alkyl-carbonyl,

(28) C₃₋₆ cycloalkyl-carbonyl,

(29) C₆₋₁₄ aryl-carbonyl optionally substituted by C₁₋₆ alkoxy,

(30) C₇₋₁₆ aralkyl-carbonyl,

(31) 5- or 6-membered heterocyclyl-carbonyl,

(32) carbamoyl,

(33) thiocarbamoyl,

(34) C₁₋₆ alkyl-carbamoyl,

(35) di(C₁₋₆)alkyl-carbamoyl,

(36) C₆₋₁₄ aryl-carbamoyl,

(37) di(C₆₋₁₄)aryl-carbamoyl,

(38) sulfamoyl,

(39) C₁₋₆ alkylsulfamoyl,

(40) di(C₁₋₆)alkylsulfamoyl,

(41) C₆₋₁₄ arylsulfamoyl,

(42) di(C₆₋₁₄)arylsulfamoyl,

(43) C₁₋₃ alkylidene optionally substituted by hydroxy,

(44) imino(═NH) optionally substituted by

(a) C₁₋₆ alkoxy optionally substituted by hydroxy, or

(b) 5- or 6-membered heterocyclyl-oxy, and the like. When the number ofthe substituents is two or more, the respective substituents may be thesame or different.

When the number of the substituents is two or more, the respectivesubstituents may be bonded to each other to form an “optionally furthersubstituted ring”.

Examples of the “ring” of the “optionally further substituted ring”include those similar to the rings of the “3- to 14-membered cyclicgroup” of the “optionally substituted 3- to 14-membered cyclic group”exemplified as the substituent of the aforementioned “substituent groupA”, such as tetrahydrofuran, pyrazole, 1,3-dioxolane, 1,3-dioxane,dihydroisoxazole (e.g., 4,5-dihydroisoxazole) and the like.

The “3- to 10-membered nonaromatic cyclic group” of the “optionallysubstituted 3- to 10-membered nonaromatic cyclic group” for R¹ or the“5- or 6-membered aromatic cyclic group” of the “optionally substituted5- or 6-membered aromatic cyclic group” for R¹ and the “optionallyfurther substituted ring” may form a fused cyclic group or a spirocyclicgroup. Examples of such fused cyclic group include2,3-dihydro-1-benzofuranyl (e.g., 2,3-dihydro-1-benzofuran-5-yl),4,5,6,7-tetrahydro-1H-indazolyl (e.g.,4,5,6,7-tetrahydro-1H-indazol-5-yl) and the like. Examples of thespirocyclic group include 1,4-dioxaspiro[4.5]dec-8-yl,1-oxaspiro[4.5]dec-8-yl, 1,5-dioxaspiro[5.5]undec-9-yl,1-oxa-2-azaspiro[4.5]dec-2-en-8-yl,tetrahydrospiro[cyclohexane-1,2′-furo[3,4-d][1,3]dioxol]-4-yl and thelike.

The “ring” of the “optionally further substituted ring” optionally has 1to 5, preferably 1 to 3, substituents at substitutable positions.Examples of such substituent include those similar to the substituentsthat the “3- to 10-membered nonaromatic cyclic group” of the “optionallysubstituted 3- to 10-membered nonaromatic cyclic group” mentioned aboveas R¹ and the “5- or 6-membered aromatic cyclic group” of the“optionally substituted 5- or 6-membered aromatic cyclic group”mentioned above as R¹ optionally have.

The “optionally substituted 3- to 10-membered nonaromatic cyclic group”for R¹ is preferably a 3- to 10-membered nonaromatic cyclic group (e.g.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclohexenyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl,tetrahydrofuryl, thioranyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl,thiazolidinyl, piperidyl, tetrahydropyranyl, tetrahydrothiopyranyl,tetrahydroindazolyl, morpholinyl, thiomorpholinyl, piperazinyl,adamantyl, oxepanyl and the like, preferably cyclobutyl, cyclohexyl,cyclohexenyl, tetrahydrofuryl, piperidyl (e.g., piperidin-4-yl),tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydroindazolyl (e.g.,4,5,6,7-tetrahydroindazol-5-yl), adamantyl, oxepanyl (e.g.,oxepan-4-yl)) optionally substituted by 1 to 3 substituents selectedfrom the group consisting of

(1) oxo,

(2) hydroxy,

(3) amino optionally substituted by 1 or 2 substituents selected from

(a) C₁₋₆ alkyl, and

(b) a 5- or 6-membered heterocyclic group,

(4) cyano,

(5) C₁₋₆ alkyl optionally substituted by 1 to 3 substituents selectedfrom

(a) hydroxy,

(b) a halogen atom,

(c) C₁₋₆ alkoxy, and

(d) a 5- or 6-membered heterocyclic group,

(6) C₂₋₆ alkenyl optionally substituted by hydroxyl,

(7) C₆₋₁₄ aryl optionally substituted by hydroxy,

(8) C₇₋₁₆ aralkyl,

(9) a heterocyclic group optionally substituted by C₁₋₆ alkyl,

(10) C₁₋₆ alkoxy optionally substituted by 1 to 4 substituents selectedfrom

(a) a halogen atom,

(b) hydroxy,

(c) C₃₋₆ cycloalkyl optionally substituted by 1 to 3 substituentsselected from the group consisting of C₁₋₆ alkyl optionally substitutedby hydroxy, hydroxy, oxo, carbamoyl and cyano,

(d) C₂₋₆ alkenyl,

(e) C₁₋₆ alkoxy,

(f) cyano,

(g) C₁₋₆ alkyl-carbonyl optionally substituted by 1 to 3 halogen atoms,

(h) C₃₋₁₀ cycloalkyl-carbonyl,

(i) carbamoyl,

(j) C₁₋₆ alkoxyimino,

(k) C₁₋₆ alkylthio,

(l) C₁₋₆ alkylsulfonyl,

(m) C₁₋₆ alkylcarbonyloxy,

(n) C₃₋₆ cycloalkyloxy optionally substituted by hydroxy, and

(o) a 5- or 6-membered heterocyclic group optionally substituted by 1 to3 substituents selected from the group consisting of C₁₋₆ alkyl, hydroxyand oxo,

(11) C₂₋₆ alkenyloxy optionally substituted by hydroxy,

(12) C₃₋₁₀ cycloalkyloxy optionally substituted by 1 to 3 substituentsselected from the group consisting of

(a) oxo,

(b) hydroxy, and

(c) C₁₋₆ alkyl optionally substituted by hydroxy,

(13) C₆₋₁₄ aryloxy optionally substituted by 1 to 3 substituentsselected from

(a) hydroxy,

(b) C₁₋₆ alkyl optionally substituted by hydroxy,

(c) C₁₋₆ alkyl-carbonyl, and

(d) C₁₋₆ alkoxy,

(14) 5- or 6-membered heterocyclyl-oxy optionally substituted by 1 to 3substituents selected from

(a) hydroxy, and

(b) C₁₋₆ alkyl,

(15) C₁₋₆ alkyl-carbonyloxy optionally substituted by 1 to 3substituents selected from

(a) hydroxy, and

(b) C₁₋₆ alkyl-carbonyloxy,

(16) carboxy optionally substituted by C₁₋₆ alkoxy,

(17) C₁₋₆ alkyl-carbonyl,

(18) C₆₋₁₄ aryl-carbonyl optionally substituted by C₁₋₆ alkoxy,

(19) 5- or 6-membered heterocyclyl-carbonyl,

(20) carbamoyl,

(21) C₁₋₃ alkylidene optionally substituted by hydroxy,

(22) imino (═NH) optionally substituted by

(a) C₁₋₆ alkoxy optionally substituted by hydroxy, or

(b) 5- or 6-membered heterocyclyl-oxy, and the like (hereinaftersometimes to be abbreviated as substituent group B). When the number ofthe substituents is two or more, the respective substituents may be thesame or different.

The “optionally substituted 5- or 6-membered aromatic cyclic group” forR¹ is preferably a 5- or 6-membered aromatic cyclic group (preferably,phenyl, thienyl) optionally substituted by 1 to 3 substituents selectedfrom the group consisting of

(1) a halogen atom,

(2) C₁₋₆ alkyl optionally substituted by hydroxy,

(3) C₁₋₆ alkoxy optionally substituted by 1 to 3 substituents selectedfrom

(a) hydroxy, and

(b) C₁₋₆ alkyl-carbonyl,

(4) C₁₋₆ alkyl-carbonyl,

and the like. When the number of the substituents is two or more, therespective substituents may be the same or different.

R¹ is preferably optionally substituted C₁₋₆ alkyl, an optionallysubstituted 3- to 10-membered nonaromatic ring or an optionallysubstituted 5- or 6-membered aromatic ring, more preferably anoptionally substituted 3- to 10-membered nonaromatic ring.

R¹ is more preferably C₃₋₈ cycloalkyl optionally substituted by C₁₋₆alkoxy optionally substituted by

1) a halogen atom,

2) cyano,

3) hydroxy, or

4) C₁₋₆ alkoxy optionally substituted by a halogen atom. When the numberof the substituents is two or more, the respective substituents may bethe same or different.

Examples of the “C₃₋₈ cycloalkyl” include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and the like.

R¹ is particularly preferably cyclohexyl optionally substituted by C₁₋₆alkoxy (e.g., isobutoxy, —OCH(CH₃)(CH(CH₃)₂) etc.) optionallysubstituted by hydroxy. When the number of the substituents is two ormore, the respective substituents may be the same or different.

R² is a hydrogen atom, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₁₋₆ alkoxy, optionally substituted C₁₋₆ alkylthio,optionally substituted C₁₋₆ alkylsulfinyl or optionally substituted C₁₋₆alkylsulfonyl.

Examples of the substituent of the “C₁₋₆ alkylsulfinyl” of the“optionally substituted C₁₋₆ alkylsulfinyl” and the “C₁₋₆ alkylsulfonyl”of the “optionally substituted C₁₋₆ alkylsulfonyl” for R² include 1 to5, preferably 1 to 3, substituents selected from those exemplified asthe substituents of the aforementioned “substituent group A”. When thenumber of the substituents is two or more, the respective substituentsmay be the same or different.

R² is preferably optionally substituted C₁₋₆ alkyl.

R² is more preferably C₁₋₆ alkyl (e.g., methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,neopentyl, tert-pentyl, hexyl), and particularly preferably propyl,butyl or pentyl.

R³ is a hydrogen atom, a halogen atom, optionally substituted C₁₋₆ alkylor optionally substituted C₁₋₆ alkoxy.

R³ is preferably a hydrogen atom or a halogen atom (preferably, fluorineatom), and particularly preferably a hydrogen atom.

W is optionally substituted C₁₋₄ alkylene, —O—W′—, —W′—O—, —N(Ra)—W′— or—W′—N(Ra)— wherein W′ is a bond or optionally substituted C₁₋₄ alkylene,and Ra is a hydrogen atom, optionally substituted C₁₋₆ alkyl oroptionally substituted C₃₋₆ cycloalkyl.

The “C₁₋₄ alkylene” of the “optionally substituted C₁₋₄ alkylene” for Wor W′ may be a straight chain or a branched chain and, for example,methylene, ethylene, —(CH₂)₃—, —(CH₂)₄—, —CH(CH₃)—, —C(CH₃)₂—,—CH(CH₃)—CH₂—, —CH₂—CH(CH₃)—, —C(CH₃)₂—CH₂—, —CH₂—C(CH₃)₂— and the like.

The “C₁₋₄ alkylene” of the “optionally substituted C₁₋₄ alkylene” for Wor W′ may have 1 to 3 substituents at substitutable positions. Examplesof such substituent include a halogen atom (e.g., fluorine atom,chlorine atom, bromine atom etc.), oxo, hydroxy, nitro, cyano,optionally halogenated C₁₋₆ alkoxy (e.g., methoxy, ethoxy,trifluoromethoxy etc.), amino, C₁₋₆ alkylamino (e.g., methylamino etc.),di(C₁₋₆)alkylamino (e.g., dimethylamino etc.), C₁₋₆ alkylcarbonylamino(e.g., acetylamino etc.) and the like. When the number of thesubstituents is two or more, the respective substituents may be the sameor different.

Preferable examples of the “optionally substituted C₁₋₆ alkyl” for Rainclude C₁₋₆ alkyl and the like.

The “C₃₋₆ cycloalkyl” of the “optionally substituted C₃₋₆ cycloalkyl”for Ra is optionally substituted by 1 to 5, preferably 1 to 3,substituents selected from the substituent groups exemplified as thesubstituents of the aforementioned “substituent group B”. When thenumber of the substituents is two or more, the respective substituentsmay be the same or different.

Preferable examples of the “optionally substituted C₃₋₆ cycloalkyl” forRa include C₃₋₆ cycloalkyl and the like.

W is preferably C₁₋₄ alkylene, more preferably methylene, ethylene or—CH(CH₃)—, and particularly preferably methylene.

A is an optionally substituted 5- or 6-membered divalent aromatic ring.

Examples of the “5- or 6-membered divalent aromatic ring” of the“optionally substituted 5- or 6-membered divalent aromatic ring” for Ainclude phenylene, furan-di-yl, thiophene-di-yl, pyrrole-di-yl,oxazole-di-yl, isoxazole-di-yl, triazole-di-yl, isothiazole-di-yl,imidazole-di-yl, pyrazole-di-yl, 1,2,3-oxadiazole-di-yl,1,2,4-oxadiazole-di-yl, 1,3,4-oxadiazole-di-yl, furazan-di-yl,1,2,3-thiadiazole-di-yl, 1,2,4-thiadiazole-di-yl,1,3,4-thiadiazole-di-yl, 1,2,3-triazole-di-yl, 1,2,4-triazole-di-yl,tetrazole-di-yl, pyridine-di-yl, pyridazine-di-yl, pyrimidine-di-yl,pyrazine-di-yl, triazine-di-yl and the like.

The “5- or 6-membered divalent aromatic ring” of the “optionallysubstituted 5- or 6-membered divalent aromatic ring” for A optionallyhas 1 to 4, preferably 1 to 3, substituents at substitutable positions.Examples of such substituent include those similar to the substituentsthat the “3- to 10-membered nonaromatic cyclic group” of the “optionallysubstituted 3- to 10-membered nonaromatic cyclic group” mentioned aboveas R¹ and the “5- or 6-membered aromatic cyclic group” of the“optionally substituted 5- or 6-membered aromatic cyclic group”mentioned above as R¹ optionally have. When the number of thesubstituents is two or more, the respective substituents may be the sameor different.

When the number of the substituents is two or more, the respectivesubstituents may be bonded to each other to further form a ring.Examples of such ring include those similar to the rings of the “3- to14-membered cyclic group” of the “optionally substituted 3- to14-membered cyclic group” exemplified as the substituents of theaforementioned “substituent group A”.

The “5- or 6-membered divalent aromatic ring” of the “optionallysubstituted 5- or 6-membered divalent aromatic ring” for A and said ringmay form a fused ring.

Examples of such fused ring include benzothiophene, benzofuran,naphthalene, quinoline, indole and the like.

The “fused ring” optionally has 1 to 5, preferably 1 to 3, substituentsat substitutable positions. Examples of such substituent include thosesimilar to the substituents that the “3- to 10-membered nonaromaticcyclic group” of the “optionally substituted 3- to 10-memberednonaromatic cyclic group” mentioned above as R¹ and the “5- or6-membered aromatic cyclic group” of the “optionally substituted 5- or6-membered aromatic cyclic group” mentioned above as R¹ optionally have.When the number of the substituents is two or more, the respectivesubstituents may be the same or different.

A is preferably optionally substituted phenylene, optionally substitutedthiophene-di-yl or optionally substituted pyridine-di-yl. Examples ofthe substituent of the optionally substituted phenylene, optionallysubstituted thiophene-di-yl or optionally substituted pyridine-di-ylinclude those similar to the aforementioned substituents exemplified asthe substituents of the “3- to 10-membered nonaromatic cyclic group” ofthe “optionally substituted 3- to 10-membered nonaromatic cyclic group”for R¹ and the “5- or 6-membered aromatic cyclic group” of the“optionally substituted 5- or 6-membered aromatic cyclic group” for R¹.When the number of the substituents is two or more, the respectivesubstituents may be the same or different.

A is more preferably phenylene, thiophene-di-yl or pyridine-di-yl(preferably, 1,4-phenylene, 2,5-thiophene-di-yl, 3,6-pyridine-di-yl)optionally substituted by 1 to 3 (preferably 1 or 2) substituentsselected from

(1) a halogen atom (preferably, fluorine atom),

(2) nitro,

(3) C₁₋₆ alkyl optionally substituted by 1 to 3 halogen atoms(preferably, methyl, trifluoromethyl), and

(4) C₁₋₆ alkoxy (preferably, methoxy). When the number of thesubstituents is two or more, the respective substituents may be the sameor different.

Particularly preferred is phenylene optionally substituted by a halogenatom (preferably, fluorine atom).

B is acyl or an optionally substituted 3- to 10-membered heterocyclicgroup.

The “acyl” for B is, for example, a group represented by the formula:—COR^(A), —CO—OR^(A), —SO₂R^(A), —SOR^(A), —CO—NR^(A′)R^(B′) or—CS—NR^(A′)R^(B′) wherein R^(A) is a hydrogen atom, hydroxy, anoptionally substituted hydrocarbon group, an optionally substitutedamino or an optionally substituted heterocyclic group; and R^(A′) andR^(B′) are each a hydrogen atom, an optionally substituted hydrocarbongroup or an optionally substituted heterocyclic group, or R^(A′) andR^(B′) may form, together with the nitrogen atom bonded thereto, anoptionally substituted nitrogen-containing heterocycle and the like.

Examples of the “hydrocarbon group” of the “optionally substitutedhydrocarbon group” for R^(A), R^(A′) or R^(B′) include C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₃ alkylidene, C₃₋₁₀-cycloalkyl, C₃₋₁₀cycloalkenyl (e.g., cyclopentenyl, cyclohexenyl etc.), C₄₋₁₀cycloalkadienyl (e.g., 2,4-cyclopentadienyl, 1,3-cyclohexadienyl etc.),C₆₋₁₄ aryl, C₇₋₁₆ aralkyl, C₈₋₁₃ arylalkenyl (e.g., phenylethyl,phenylpropionyl etc.), C₃₋₁₀ cycloalkyl (e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl etc.) —C₁₋₆ alkyl (e.g., methyl, ethyl, propyl,butyl etc.) and the like.

The “hydrocarbon group” of the “optionally substituted hydrocarbongroup” and the “amino” of the “optionally substituted amino” for R^(A),R^(A′) or R^(B′) may be each substituted by, 1 to 5, preferably 1 to 3,substituents selected from the aforementioned “substituent group A”.

The “heterocyclic group” of the “optionally substituted heterocyclicgroup” for R^(A), R^(A′) or R^(B′) optionally has 1 to 5, preferably 1to 3, substituents at substitutable positions. Examples of suchsubstituent include those similar to the aforementioned substituentsexemplified as the substituents of the “3- to 10-membered nonaromaticcyclic group” of the “optionally substituted 3- to 10-memberednonaromatic cyclic group” for R¹ and the “5- or 6-membered aromaticcyclic group” of the “optionally substituted 5- or 6-membered aromaticcyclic group” for R¹.

Examples of the “nitrogen-containing heterocycle” of the “optionallysubstituted nitrogen-containing heterocycle” optionally formed by R^(A′)and R^(B′) together with the nitrogen atom bonded thereto includeazetidine, pyrrolidine, imidazolidine, pyrazolidine, piperidine,homopiperidine, piperazine, homopiperazine, morpholine, homomorpholine,thiomorpholine, thiohomomorpholine, dihydrobenzoxazine (e.g.,3,4-dihydro-2H-1,4-benzoxazine), 1,2,3,4-tetrahydroquinoline,7-aza-bicyclo[2.2.1]heptane and the like.

The “nitrogen-containing heterocycle” optionally has 1 to 5, preferably1 to 3, substituents at substitutable positions. Examples of suchsubstituent include those similar to the aforementioned substituentsexemplified as the substituents of the “3- to 10-membered nonaromaticcyclic group” of the “optionally substituted 3- to 10-memberednonaromatic cyclic group” for R¹ and the “5- or 6-membered aromaticcyclic group” of the “optionally substituted 5- or 6-membered aromaticcyclic group” for R¹. When the number of the substituents is two ormore, the respective substituents may be the same or different.

Examples of the “3- to 10-membered heterocyclic group” of the“optionally substituted 3- to 10-membered heterocyclic group” for Binclude a 3- to 10-membered (preferably, 5- or 6-membered) monocyclicheterocyclic group (preferably, nitrogen-containing heterocyclic grouphaving a protonizable hydrogen atom), which contains one or more from anitrogen atom, an oxygen atom and a sulfur atom (preferably, nitrogenatom), or a group that can be converted to such group. Examples of the“3- to 10-membered heterocyclic group” include groups represented by thefollowing formulas:

wherein g is —CH₂—, —NR⁹—, —O— or —S(O)_(m)— wherein m is an integer of0, 1 or 2 and R⁹ is a hydrogen atom or optionally substituted C₁₋₆alkyl; and Z¹, Z² and Z³ are each independently an oxygen atom oroptionally oxidized sulfur atom (preferably an oxygen atom or a sulfuratom, more preferably an oxygen atom), and the like.

The bond of “3- to 10-membered heterocyclic group” of the “optionallysubstituted 3- to 10-membered heterocyclic group” for B and phenyl maybe not only the carbon-carbon bond shown in the above-mentioned formulasbut also a bond via one nitrogen atom when the “3- to 10-memberedheterocyclic group” contains plural nitrogen atoms.

For example, when the “3- to 10-membered heterocyclic group” is

wherein each symbol is as defined above, the bond specifically includes

wherein each symbol is as defined above, and the like. Examples of other“3- to 10-membered heterocyclic group” bonded via a nitrogen atominclude groups represented by

wherein each symbol is as defined above, and the like.

The “3- to 10-membered heterocyclic group” is preferably a groupsimultaneously having an —NH group or —OH group as a proton donor, andcarbonyl, thiocarbonyl, sulfinyl and the like as a proton acceptor suchas oxadiazole and thiadiazole. As the “3- to 10-membered heterocyclicgroup”, 5- or 6-membered (more preferably 5-membered) monocyclicheterocyclic group is preferable.

The “3- to 10-membered heterocyclic group” is preferably a grouprepresented by the formula:

wherein i is —O— or —S—, j is —C(═O)—, —C(═S)— or —S(O)_(m)—, and m isan integer of 0, 1 or 2(preferably, 4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl,4,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl,4,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl).

The “3- to 10-membered heterocyclic group” is more preferably a grouprepresented by the formula:

wherein Z⁴ is an oxygen atom or a sulfur atom.

The “3- to 10-membered heterocyclic group” can have a tautomer. When,for example, Z¹=O, g=O in the following formula:

3 tautomers of a′, b′ and c′ below

are present. In the present specification, when the “3- to 10-memberedheterocyclic group” is, for example, represented by the followingformula:

the group contains any tautomer of the above-mentioned a′, b′ and c′.Similarly, the aforementioned various “3- to 10-membered heterocyclicgroups” also contains any of such possible tautomers.

The “3- to 10-membered heterocyclic group” of the “optionallysubstituted 3- to 10-membered heterocyclic group” for B optionally has 1to 5, preferably 1 to 3, substituents at substitutable positions. Whenthe number of the substituents is two or more, the respectivesubstituents may be the same or different.

For example, when the “3- to 10-membered heterocyclic group” isrepresented by the following formula:

the group optionally has substituents at the positions shown by thefollowing formulas:

wherein R¹⁰ is a substituent. Similarly, the aforementioned various “3-to 10-membered heterocyclic groups” optionally have 1 to 5, preferably 1to 3, substituents at substitutable positions in all tautomers thereof.

Examples of the substituent that the “3- to 10-membered heterocyclicgroup” optionally has include a group represented by the formula—CH(R¹¹)—OCOR¹² wherein R¹¹ is a hydrogen atom, C₁₋₆ alkyl (e.g.,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl etc.), C₂₋₆ alkenyl or C₃₋₈cycloalkyl (e.g., cyclopentyl, cyclohexyl, cycloheptyl etc.), and R¹² isC₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl etc.), C₂₋₆ alkenyl,C₃₋₈ cycloalkyl (e.g., cyclopentyl, cyclohexyl, cycloheptyl etc.), C₁₋₃alkyl substituted by C₃₋₈ cycloalkyl (e.g., cyclopentyl, cyclohexyl,cycloheptyl etc.) or optionally substituted C₆₋₁₄ aryl (e.g., phenyletc.) (e.g., benzyl, p-chlorobenzyl, phenethyl, cyclopentylmethyl,cyclohexylmethyl etc.), C₂₋₃ alkenyl (e.g., vinyl, propenyl, allyl,isopropenyl etc.) substituted by C₃₋₈ cycloalkyl or optionallysubstituted C₆₋₁₄ aryl (e.g., phenyl etc.) (e.g., cinnamyl etc.),optionally substituted C₆₋₁₄ aryl (e.g., phenyl, p-tolyl, naphthyletc.), C₁₋₆ alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy,neopentyloxy etc.), C₂₋₈ alkenyloxy (e.g., allyloxy, isobutenyloxyetc.), C₃₋₈ cycloalkyloxy (e.g., cyclopentyloxy, cyclohexyloxy,cycloheptyloxy etc.), C₁₋₃ alkoxy (e.g., methoxy, ethoxy, propoxy,isopropoxy) substituted by C₃₋₈ cycloalkyl (e.g., cyclopentyl,cyclohexyl, cycloheptyl etc.) or optionally substituted C₆₋₁₄ aryl(e.g., phenyl etc.) (e.g., benzyloxy, phenethyloxy,cyclopentylmethyloxy, cyclohexylmethyloxy etc.), C₂₋₃ alkenyloxy (e.g.,vinyloxy, propenyloxy, allyloxy, isopropenyloxy etc.) substituted byC₃₋₈ cycloalkyl (e.g., cyclopentyl, cyclohexyl, cycloheptyl etc.) oroptionally substituted C₆₋₁₄ aryl (e.g., phenyl etc.) (e.g., cinnamyloxyetc.) or optionally substituted C₆₋₁₄ aryloxy (e.g., phenoxy,p-nitrophenoxy, naphthoxy etc.; optionally substituted alkyl (e.g., C₁₋₆alkyl) (e.g., methyl, trichloromethyl, trifluoromethyl, triphenylmethyletc.); optionally substituted acyl (e.g., C₂₋₅ alkanoyl, optionallysubstituted benzoyl etc.); a halogen atom (e.g., fluorine atom, chlorineatom, bromine atom etc.); nitro; cyano; C₁₋₆ alkoxy; amino; C₁₋₆alkylamino (e.g., methylamino etc.); di(C₁₋₆ alkyl)amino (e.g.,dimethylamino etc.) and the like.

Specific examples of the substituent include ally, methyl, ethyl,propyl, tert-butyl, methoxymethyl, triphenylmethyl, cyanoethyl, acetyl,propionyl, pivaloyloxymethyl, 1-(cyclohexyloxycarbonyloxy)ethyl,5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl, acetoxymethyl,propionyloxymethyl, butyryloxymethyl, isobutyryloxymethyl,1-(ethoxycarbonyloxy)ethyl, 1-(acetyloxy)ethyl, 1-(isobutyryloxy)ethyl,cyclohexylcarbonyloxymethyl, benzoyloxymethyl, cinnamyl,cyclopentylcarbonyloxymethyl and the like. As the substituent, thoseeasily removed under biological, namely, physiological conditions (e.g.,biological reactions such as oxidation, reduction or hydrolysis and thelike by enzymes in the body etc.), or chemically are preferable.

B is preferably an optionally substituted 3- to 10-membered heterocyclicgroup, and more preferably a 3- to 10-membered heterocyclic group.Particularly preferred are groups represented by the following formulas:

X, Y and Z are each independently CR⁴ wherein R⁴ is a hydrogen atom, ahalogen atom, optionally substituted C₁₋₆ alkyl, optionally substitutedC₁₋₆ alkoxy or optionally substituted C₃₋₆ cycloalkyl, or a nitrogenatom.

The “C₃₋₆ cycloalkyl” of the “optionally substituted C₃₋₆ cycloalkyl”for R⁴ is optionally substituted by 1 to 5, preferably 1 to 3,substituents selected from the substituent groups exemplified as thesubstituents of the aforementioned “substituent group B”. When thenumber of the substituents is two or more, the respective substituentsmay be the same or different.

R⁴ is preferably (a) a hydrogen atom; (b) a halogen atom (preferably,fluorine atom); (c) C₁₋₆ alkyl optionally substituted by 1 to 3substituents selected from the group consisting of hydroxy, a halogenatom (e.g., fluorine atom, bromine atom) and C₁₋₆ alkoxy (e.g., methoxy)(e.g., methyl, bromomethyl, trifluoromethyl, hydroxymethyl,methoxymethyl); (d) C₃₋₆ cycloalkyl (e.g., cyclopropyl), and the like.When the number of the substituents is two or more, the respectivesubstituents may be the same or different.

Preferably, X is a nitrogen atom, Y and Z are CR⁴ wherein R⁴ is (a) ahydrogen atom; (b) a halogen atom (preferably, fluorine atom); (c) C₁₋₆alkyl optionally substituted by 1 to 3 substituents selected from thegroup consisting of hydroxy, a halogen atom (e.g., fluorine atom,bromine atom) and C₁₋₆ alkoxy (e.g., methoxy) (e.g., methyl,bromomethyl, trifluoromethyl, hydroxymethyl, methoxymethyl); (d) C₃₋₆cycloalkyl (e.g., cyclopropyl) and the like. When the number of thesubstituents is two or more, the respective substituents may be the sameor different.

In another preferable embodiment, X and Z are nitrogen atoms, Y is CR⁴wherein R⁴ is (a) a hydrogen atom; (b) a halogen atom (preferably,fluorine atom); (c) C₁₋₆ alkyl optionally substituted by 1 to 3substituents selected from the group consisting of hydroxy, a halogenatom (e.g., fluorine atom, bromine atom) and C₁₋₆ alkoxy (e.g., methoxy)(e.g., methyl, bromomethyl, trifluoromethyl, hydroxymethyl,methoxymethyl); (d) C₃₋₆ cycloalkyl (e.g., cyclopropyl) and the like.When the number of the substituents is two or more, the respectivesubstituents may be the same or different.

In another preferable embodiment, X and Y are nitrogen atoms, Z is CR⁴wherein R⁴ is (a) a hydrogen atom; (b) a halogen atom (preferably,fluorine atom); (c) C₁₋₆ alkyl optionally substituted by 1 to 3substituents selected from the group consisting of hydroxy, a halogenatom (e.g., fluorine atom, bromine atom) and C₁₋₆ alkoxy (e.g., methoxy)(e.g., methyl, bromomethyl, trifluoromethyl, hydroxymethyl,methoxymethyl); (d) C₃₋₆ cycloalkyl (e.g., cyclopropyl) and the like.When the number of the substituents is two or more, the respectivesubstituents may be the same or different.

In another preferable embodiment, X is CR⁴ wherein R⁴ is (a) a hydrogenatom; (b) a halogen atom (preferably, fluorine atom); (c) C₁₋₆ alkyloptionally substituted by 1 to 3 substituents selected from the groupconsisting of hydroxy, a halogen atom (e.g., fluorine atom, bromineatom) and C₁₋₆ alkoxy (e.g., methoxy) (e.g., methyl, bromomethyl,trifluoromethyl, hydroxymethyl, methoxymethyl); (d) C₃₋₆ cycloalkyl(e.g., cyclopropyl) and the like. When the number of the substituents istwo or more, the respective substituents may be the same or different,and Y and Z are nitrogen atoms.

The parts shown by the following formulas in a compound represented bythe formula (I) may contain tautomers shown below.

All these tautomers are all encompassed in the scope of a compoundrepresented by the formula (I).

Preferable embodiments of a compound represented by the formula (I) arethe following compounds.

[Compound A1]

a compound represented by the formula:

whereinR¹ is a hydrogen atom, optionally substituted C₁₋₆ alkyl, an optionallysubstituted 3- to 10-membered nonaromatic ring or an optionallysubstituted 5- or 6-membered aromatic ring,R² is optionally substituted C₁₋₆ alkyl,R³ is a hydrogen atom or a halogen atom,W is C₁₋₄ alkylene,A is optionally substituted phenylene, optionally substitutedthiophene-di-yl or optionally substituted pyridine-di-yl,B is a group represented by the formula:

wherein i is —O— or —S—, j is —C(═O)—, —C(═S)— or —S(O)_(m)—, and m isan integer of 0, 1 or 2 (preferably,4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl,4,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl,4,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl), or tetrazolyl andtwo R⁴ are each independently a hydrogen atom, a halogen atom,optionally substituted C₁₋₆ alkyl, optionally substituted C₁₋₆ alkoxy oroptionally substituted C₃₋₆ cycloalkyl, or a salt thereof.[Compound A2]

A compound represented by the formula:

wherein R¹ is[1] a hydrogen atom,[2] C₁₋₆ alkyl optionally substituted by 1 to 5 substituents selectedfrom the group consisting of

(1) a halogen atom,

(2) hydroxy,

(3) optionally halogenated C₁₋₆ alkoxy,

(4) carboxy optionally substituted by C₁₋₆ alkoxy,

(5) C₁₋₆ alkyl-carbonyl optionally substituted by 1 to 3 halogen atoms,

(6) C₃₋₁₀ cycloalkyl-carbonyl,

(7) C₆₋₁₄ aryl-carbonyl optionally substituted by 1 to 3 halogen atoms,

(8) carbamoyl,

(9) a 3- to 14-membered cyclic group (preferably, cyclopropyl,cyclohexyl, phenyl, pyridyl, oxetanyl, benzimidazolyl (e.g.,benzimidazol-2-yl)) optionally substituted by 1 to 3 substituentsselected from the group consisting of (a) a halogen atom, (b) C₁₋₆ alkyloptionally substituted by hydroxy, (c) C₆₋₁₄ aryl, (d) C₁₋₆ alkoxy and(e) C₁₋₆ alkyl-carbonyl, and

(10) C₁₋₆ alkoxyimino,

[3] a 3- to 10-membered nonaromatic cyclic group (preferably,cyclobutyl, cyclohexyl (the cyclohexyl may form, together with the ringformed by two substituents, a spirocyclic group (e.g.,1,4-dioxaspiro[4.5]dec-8-yl)), cyclohexenyl, tetrahydrofuryl, piperidyl(e.g., piperidin-4-yl), tetrahydropyranyl, tetrahydrothiopyranyl,tetrahydroindazolyl (e.g., 4,5,6,7-tetrahydroindazol-5-yl), adamantyl,oxepanyl (e.g., oxepan-4-yl)) optionally substituted by 1 to 3substituents selected from the group consisting of

(1) oxo,

(2) hydroxy,

(3) amino optionally substituted by 1 or 2 substituents selected from

-   -   (a) C₁₋₆ alkyl, and    -   (b) a 5- or 6-membered heterocyclic group,

(4) cyano,

(5) C₁₋₆ alkyl optionally substituted by 1 to 3 substituents selectedfrom

-   -   (a) hydroxy,    -   (b) a halogen atom,    -   (c) C₁₋₆ alkoxy, and    -   (d) a 5- or 6-membered heterocyclic group,

(6) C₆₋₁₄ aryl optionally substituted by hydroxy,

(7) C₇₋₁₆ aralkyl,

(8) a heterocyclic group optionally substituted by C₁₋₆ alkyl,

(9) C₁₋₆ alkoxy optionally substituted by 1 to 4 substituents selectedfrom

-   -   (a) a halogen atom,    -   (b) hydroxy,    -   (c) C₃₋₆ cycloalkyl optionally substituted by 1 to 3        substituents selected from the group consisting of C₁₋₆ alkyl        optionally substituted by hydroxy, hydroxy, carbamoyl and cyano,    -   (d) C₁₋₆ alkoxy,    -   (e) cyano,    -   (f) C₁₋₆ alkyl-carbonyl optionally substituted by 1 to 3 halogen        atoms,    -   (g) C₃₋₁₀ cycloalkyl-carbonyl,    -   (h) carbamoyl,    -   (i) C₁₋₆ alkoxyimino,    -   (j) C₁₋₆ alkylthio,    -   (k) C₁₋₆ alkylsulfonyl,    -   (l) C₁₋₆ alkylcarbonyloxy,    -   (m) C₃₋₆ cycloalkyloxy optionally substituted by hydroxy, and    -   (n) a 5- or 6-membered heterocyclic group optionally substituted        by 1 to 3 substituents selected from the group consisting of        C₁₋₆ alkyl and oxo,

(10) C₂₋₆ alkenyloxy optionally substituted by hydroxy,

(11) C₃₋₁₀ cycloalkyloxy optionally substituted by 1 to 3 substituentsselected from the group consisting of

-   -   (a) oxo,    -   (b) hydroxy, and    -   (c) C₁₋₆ alkyl optionally substituted by hydroxy,

(12) C₆₋₁₄ aryloxy optionally substituted by 1 to 3 substituentsselected from

-   -   (a) hydroxy,    -   (b) C₁₋₆ alkyl optionally substituted by hydroxy,    -   (c) C₁₋₆ alkyl-carbonyl, and    -   (d) C₁₋₆ alkoxy,

(13) 5- or 6-membered heterocyclyl-oxy optionally substituted by 1 to 3substituents selected from

-   -   (a) hydroxy, and    -   (b) C₁₋₆ alkyl,

(14) C₁₋₆ alkyl-carbonyloxy optionally substituted by 1 to 3substituents selected from

-   -   (a) hydroxy, and    -   (b) C₁₋₆ alkyl-carbonyloxy,

(15) carboxy optionally substituted by C₁₋₆ alkoxy,

(16) C₁₋₆ alkyl-carbonyl,

(17) C₆₋₁₄ aryl-carbonyl optionally substituted by C₁₋₆ alkoxy,

(18) 5- or 6-membered heterocyclyl-carbonyl,

(19) carbamoyl,

(20) C₁₋₃ alkylidene optionally substituted by hydroxy, and

(21) imino (═NH) optionally substituted by

-   -   (a) C₁₋₆ alkoxy optionally substituted by hydroxy, or    -   (b) 5- or 6-membered heterocyclyl-oxy, or        [4] a 5- or 6-membered aromatic cyclic group (preferably,        phenyl, thienyl) optionally substituted by 1 to 3 substituents        selected from the group consisting of

(1) a halogen atom,

(2) C₁₋₆ alkyl optionally substituted by hydroxy,

(3) C₁₋₆ alkoxy optionally substituted by 1 to 3 substituents selectedfrom

-   -   (a) hydroxy, and    -   (b) C₁₋₆ alkyl-carbonyl, and

(4) C₁₋₆ alkyl-carbonyl,

R² is C₁₋₆ alkyl,

R³ is a hydrogen atom or a halogen atom,

W is C₁₋₄ alkylene,

A is phenylene, thiophene-di-yl or pyridine-di-yl optionally substitutedby 1 to 3 (preferably 1 or 2) substituents selected from the groupconsisting of

(1) a halogen atom,

(2) nitro,

(3) C₁₋₆ alkyl optionally substituted by 1 to 3 halogen atoms, and

(4) C₁₋₆ alkoxy,

B is a group represented by the formula:

wherein Z⁴ is an oxygen atom or a sulfur atom, or tetrazolyl, andtwo R⁴ are each independently (a) a hydrogen atom, (b) a halogen atom,(c) C₁₋₆ alkyl optionally substituted by 1 to 3 substituents selectedfrom the group consisting of hydroxy, a halogen atom and C₁₋₆ alkoxy or(d) C₃₋₆ cycloalkyl, or a salt thereof.[Compound A3]

A group represented by the formula:

whereinR¹ is[1] a 3- to 10-membered nonaromatic cyclic group (preferably, cyclohexyl(the cyclohexyl may form, together with the ring formed by twosubstituents, a spirocyclic group (e.g., 1,4-dioxaspiro[4.5]dec-8-yl)),tetrahydropyranyl) optionally substituted by 1 to 3 substituentsselected from the group consisting of

(1) oxo,

(2) hydroxy,

(3) C₁₋₆ alkoxy optionally substituted by 1 to 4 substituents selectedfrom

-   -   (a) a halogen atom,    -   (b) hydroxy,    -   (c) C₃₋₆ cycloalkyl optionally substituted by hydroxy,    -   (d) C₁₋₆ alkyl-carbonyl optionally substituted by 1 to 3 halogen        atoms, and    -   (e) C₃₋₁₀ cycloalkyl-carbonyl,

(4) C₃₋₁₀ cycloalkyloxy optionally substituted by 1 to 3 substituentsselected from the group consisting of

-   -   (a) hydroxy, and    -   (b) C₁₋₆ alkyl, and

(5) C₁₋₆ alkyl-carbonyloxy optionally substituted by 1 to 3 substituentsselected from

-   -   (a) hydroxy, and    -   (b) C₁₋₆ alkyl-carbonyloxy, or        [2] 5- or 6-membered aromatic ring (preferably, phenyl)        optionally substituted by C₁₋₆ alkoxy,        R² is C₁₋₆ alkyl,        R³ is a hydrogen atom,        W is methylene or —CH(CH₃)—,        A is phenylene or pyridine-di-yl optionally substituted by 1 to        3 (preferably 1 or 2) substituents selected from

(1) a halogen atom,

(2) nitro,

(3) C₁₋₆ alkyl, and

(4) C₁₋₆ alkoxy,

B is a group represented by the formula:

or tetrazolyl, andtwo R⁴ are each independently a hydrogen atom, a halogen atom, or C₁₋₆alkyl, or a salt thereof.[Compound A4]

A compound represented by the formula:

wherein

R¹ is C₃₋₈ cycloalkyl optionally substituted by C₁₋₆ alkoxy optionallysubstituted by

1) a halogen atom,

2) cyano,

3) hydroxy, or

4) C₁₋₆ alkoxy optionally substituted by a halogen atom,

R² is C₁₋₆ alkyl,

A is phenylene optionally substituted by a halogen atom, and

R⁴ are each independently a hydrogen atom or methyl, or a salt thereof.

[Compound A5]

A compound represented by the formula:

whereinR¹ is cyclohexyl optionally substituted by C₁₋₆ alkoxy optionallysubstituted by hydroxy, andR² is C₁₋₆ alkyl, or a salt thereof.[Compound B1]

A compound represented by the formula:

whereinR¹ is a hydrogen atom, optionally substituted C₁₋₆ alkyl, an optionallysubstituted 3- to 10-membered nonaromatic ring or an optionallysubstituted 5- or 6-membered aromatic ring,R² is optionally substituted C₁₋₆ alkyl,R³ is a hydrogen atom or a halogen atom,W is C₁₋₄ alkylene,A is optionally substituted phenylene, optionally substitutedthiophene-di-yl or optionally substituted pyridine-di-yl,B is a group represented by the formula:

wherein i is —O— or —S—, j is —C(═O)—, —C(═S)— or —S(O)_(m)—, and m isan integer of 0, 1 or 2 (preferably,4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl,4,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl,4,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl), or tetrazolyl, andR⁴ is a hydrogen atom, a halogen atom, optionally substituted C₁₋₆alkyl, optionally substituted C₁₋₆ alkoxy or optionally substituted C₃₋₆cycloalkyl, or a salt thereof.[Compound B2]

A compound represented by the formula:

whereinR¹ is[1] a hydrogen atom,[2] C₁₋₆ alkyl optionally substituted by 1 to 4 substituents selectedfrom the group consisting of

(1) a halogen atom,

(2) hydroxy,

(3) optionally halogenated C₁₋₆ alkoxy,

(4) carboxy optionally substituted by C₁₋₆ alkoxy,

(5) C₁₋₆ alkyl-carbonyl optionally substituted by 1 to 3 halogen atoms,

(6) C₃₋₁₀ cycloalkyl-carbonyl,

(7) C₆₋₁₄ aryl-carbonyl optionally substituted by 1 to 3 halogen atoms,

(8) carbamoyl,

(9) a 3- to 14-membered cyclic group (preferably, cyclopropyl,cyclohexyl, phenyl, pyridyl, oxetanyl, benzimidazolyl (e.g.,benzimidazol-2-yl)) optionally substituted by 1 to 3 substituentsselected from the group consisting of (a) a halogen atom, (b) C₁₋₆ alkyloptionally substituted by hydroxy, (c) C₆₋₁₄ aryl, (d) C₁₋₆ alkoxy and(e) C₁₋₆ alkyl-carbonyl, and

(10) C₁₋₆ alkoxyimino,

[3] a 3- to 10-membered nonaromatic cyclic group (preferably,cyclobutyl, cyclohexyl, cyclohexenyl, tetrahydrofuryl, piperidyl (e.g.,piperidin-4-yl), tetrahydropyranyl, tetrahydrothiopyranyl,tetrahydroindazolyl (e.g., 4,5,6,7-tetrahydroindazol-5-yl), adamantyl,oxepanyl (e.g., oxepan-4-yl)) optionally substituted by 1 to 3substituents selected from the group consisting of

(1) oxo,

(2) hydroxy,

(3) amino optionally substituted by 1 or 2 substituents selected from

-   -   (a) C₁₋₆ alkyl, and    -   (b) a 5- or 6-membered heterocyclic group,

(4) cyano,

(5) C₁₋₆ alkyl optionally substituted by 1 to 3 substituents selectedfrom

-   -   (a) hydroxy,    -   (b) a halogen atom,    -   (c) C₁₋₆ alkoxy, and    -   (d) a 5- or 6-membered heterocyclic group,

(6) C₆₋₁₄ aryl optionally substituted by hydroxy,

(7) C₇₋₁₆ aralkyl,

(8) a heterocyclic group optionally substituted by C₁₋₆ alkyl,

(9) C₁₋₆ alkoxy optionally substituted by 1 to 4 substituents selectedfrom

-   -   (a) a halogen atom,    -   (b) hydroxy,    -   (c) C₃₋₆ cycloalkyl optionally substituted by 1 to 3        substituents selected from the group consisting of C₁₋₆ alkyl        optionally substituted by hydroxy, hydroxy, carbamoyl and cyano,    -   (d) C₁₋₆ alkoxy,    -   (e) cyano,    -   (f) C₁₋₆ alkyl-carbonyl optionally substituted by 1 to 3 halogen        atoms,    -   (g) C₃₋₁₀ cycloalkyl-carbonyl,    -   (h) carbamoyl,    -   (i) C₁₋₆ alkoxyimino,    -   (j) C₁₋₆ alkylthio,    -   (k) C₁₋₆ alkylsulfonyl,    -   (l) C₁₋₆ alkylcarbonyloxy,    -   (m) C₃₋₆ cycloalkyloxy optionally substituted by hydroxy, and    -   (n) a 5- or 6-membered heterocyclic group optionally substituted        by 1 to 3 substituents selected from the group consisting of        C₁₋₆ alkyl and oxo,

(10) C₂₋₆ alkenyloxy optionally substituted by hydroxy,

(11) C₃₋₁₀ cycloalkyloxy optionally substituted by 1 to 3 substituentsselected from the group consisting of

-   -   (a) oxo,    -   (b) hydroxy, and    -   (c) C₁₋₆ alkyl optionally substituted by hydroxy,

(12) C₆₋₁₄ aryloxy optionally substituted by 1 to 3 substituentsselected from

-   -   (a) hydroxy,    -   (b) C₁₋₆ alkyl optionally substituted by hydroxy,    -   (c) C₁₋₆ alkyl-carbonyl, and    -   (d) C₁₋₆ alkoxy,

(13) 5- or 6-membered heterocyclyl-oxy optionally substituted by 1 to 3substituents selected from

-   -   (a) hydroxy, and    -   (b) C₁₋₆ alkyl,

(14) C₁₋₆ alkyl-carbonyloxy optionally substituted by 1 to 3substituents selected from

-   -   (a) hydroxy, and    -   (b) C₁₋₆ alkyl-carbonyloxy,

(15) carboxy optionally substituted by C₁₋₆ alkoxy,

(16) C₁₋₆ alkyl-carbonyl,

(17) C₆₋₁₄ aryl-carbonyl optionally substituted by C₁₋₆ alkoxy,

(18) 5- or 6-membered heterocyclyl-carbonyl,

(19) carbamoyl,

(20) C₁₋₃ alkylidene optionally substituted by hydroxy, and

(21) imino (═NH) optionally substituted by

-   -   (a) C₁₋₆ alkoxy optionally substituted by hydroxy, or    -   (b) 5- or 6-membered heterocyclyl-oxy, or        [4] 5- or 6-membered aromatic ring (preferably, phenyl, thienyl)        optionally substituted by 1 to 3 substituents selected from the        group consisting of

(1) a halogen atom,

(2) C₁₋₆ alkyl optionally substituted by hydroxy,

(3) C₁₋₆ alkoxy optionally substituted by 1 to 3 substituents selectedfrom

-   -   (a) hydroxy, and    -   (b) C₁₋₆ alkyl-carbonyl, and

(4) C₁₋₆ alkyl-carbonyl,

R² is C₁₋₆ alkyl,

R³ is a hydrogen atom or a halogen atom,

W is C₁₋₄ alkylene,

A is phenylene, thiophene-di-yl or pyridine-di-yl optionally substitutedby 1 to 3 (preferably 1 or 2) substituents selected from the groupconsisting of

(1) a halogen atom,

(2) nitro,

(3) C₁₋₆ alkyl optionally substituted by 1 to 3 halogen atoms, and

(4) C₁₋₆ alkoxy,

B is a group represented by the formula:

wherein Z⁴ is an oxygen atom or a sulfur atom, or tetrazolyl, andR⁴ is (a) a hydrogen atom, (b) a halogen atom, (c) C₁₋₆ alkyl optionallysubstituted by 1 to 3 substituents selected from the group consisting ofhydroxy, a halogen atom and C₁₋₆ alkoxy or (d) C₃₋₆ cycloalkyl, or asalt thereof.[Compound B3]

A compound represented by the formula:

whereinR¹ is[1] a hydrogen atom,[2] C₁₋₆ alkyl optionally substituted by 1 to 4 substituents selectedfrom the group consisting of

(1) a halogen atom,

(2) hydroxy,

(3) optionally halogenated C₁₋₆ alkoxy,

(4) carboxy optionally substituted by C₁₋₆ alkoxy,

(5) C₁₋₆ alkyl-carbonyl optionally substituted by 1 to 3 halogen atoms,

(6) C₃₋₁₀ cycloalkyl-carbonyl,

(7) C₆₋₁₄ aryl-carbonyl optionally substituted by 1 to 3 halogen atoms,

(8) carbamoyl,

(9) a 3- to 14-membered cyclic group (preferably, cyclopropyl,cyclohexyl, phenyl, pyridyl, oxetanyl, benzimidazolyl (e.g.,benzimidazol-2-yl)) optionally substituted by 1 to 3 substituentsselected from the group consisting of a halogen atom, C₁₋₆ alkyloptionally substituted by hydroxy, C₆₋₁₄ aryl, C₁₋₆ alkoxy and C₁₋₆alkyl-carbonyl, and

(10) C₁₋₆ alkoxyimino,

[3] a 3- to 10-membered nonaromatic cyclic group (e.g., cyclobutyl,cyclohexyl (the cyclohexyl may form, together with the ring formed bytwo substituents, an optionally substituted fused cyclic group or aspirocyclic group (e.g., 4,5,6,7-tetrahydro-1H-indazol-5-yl,1-oxaspiro[4.5]dec-8-yl, 1,4-dioxaspiro[4.5]dec-8-yl,1,5-dioxaspiro[5.5]undec-9-yl, 1-oxa-2-azaspiro[4.5]dec-2-en-8-yl,tetrahydrospiro[cyclohexane-1,2′-furo[3,4-d][1,3]dioxol]-4-yl, which isoptionally substituted by 1 to 5 substituents selected from the groupconsisting of oxo, hydroxy, C₁₋₆ alkyl optionally substituted byhydroxyl and C₁₋₃ alkylidene)), cyclohexenyl, tetrahydrofuryl, piperidyl(e.g., piperidin-4-yl), tetrahydropyranyl, tetrahydrothiopyranyl,tetrahydroindazolyl (e.g., 4,5,6,7-tetrahydroindazol-5-yl), adamantyl,oxepanyl (e.g., oxepan-4-yl)) optionally substituted by 1 to 3substituents selected from the group consisting of

(1) oxo,

(2) hydroxy,

(3) amino optionally substituted by 1 or 2 substituents selected from

-   -   (a) C₁₋₆ alkyl, and    -   (b) a 5- or 6-membered heterocyclic group (preferably,        tetrahydropyranyl),

(4) cyano,

(5) C₁₋₆ alkyl optionally substituted by 1 to 3 substituents selectedfrom

-   -   (a) hydroxy,    -   (b) a halogen atom,    -   (c) C₁₋₆ alkoxy, and    -   (d) a 5- or 6-membered heterocyclic group (preferably,        morpholino),

(6) C₆₋₁₄ aryl optionally substituted by hydroxy,

(7) C₇₋₁₆ aralkyl,

(8) a heterocyclic group (preferably, morpholino, 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, oxazolyl, 4,5-dihydroisoxazolyl, tetrahydropyranyl)optionally substituted by C₁₋₆ alkyl,

(9) C₁₋₆ alkoxy optionally substituted by 1 to 4 substituents selectedfrom

-   -   (a) hydroxy,    -   (b) C₃₋₆ cycloalkyl optionally substituted by 1 to 3        substituents selected from the group consisting of C₁₋₆ alkyl        optionally substituted by hydroxy, hydroxy, carbamoyl and cyano,    -   (c) C₁₋₆ alkoxy,    -   (d) cyano,    -   (e) C₁₋₆ alkyl-carbonyl optionally substituted by 1 to 3 halogen        atoms,    -   (f) carbamoyl,    -   (g) C₁₋₆ alkoxyimino,    -   (h) C₁₋₆ alkylthio,    -   (i) C₁₋₆ alkylsulfonyl,    -   (j) C₁₋₆ alkylcarbonyloxy, and    -   (k) a 5- or 6-membered heterocyclic group (preferably,        morpholino, imidazolyl, 1,3,4-oxadiazolyl,        4,5-dihydro-1,3,4-oxadiazolyl, 1,2,4-triazolyl, tetrahydrofuryl)        optionally substituted by 1 to 3 substituents selected from the        group consisting of C₁₋₆ alkyl and oxo,

(10) C₂₋₆ alkenyloxy optionally substituted by hydroxy,

(11) C₃₋₁₀ cycloalkyloxy optionally substituted by 1 to 3 substituentsselected from the group consisting of

-   -   (a) oxo,    -   (b) hydroxy, and    -   (c) C₁₋₆ alkyl optionally substituted by hydroxy,

(12) C₆₋₁₄ aryloxy optionally substituted by 1 to 3 substituentsselected from

-   -   (a) hydroxy,    -   (b) C₁₋₆ alkyl optionally substituted by hydroxy,    -   (c) C₁₋₆ alkyl-carbonyl, and    -   (d) C₁₋₆ alkoxy,

(13) 5- or 6-membered heterocyclyl-oxy (preferably, tetrahydrofuryloxy,isoxazolyloxy) optionally substituted by 1 to 3 substituents selectedfrom

-   -   (a) hydroxy, and    -   (b) C₁₋₆ alkyl,

(14) carboxy optionally substituted by C₁₋₆ alkoxy,

(15) C₆₋₁₄ aryl-carbonyl optionally substituted by C₁₋₆ alkoxy,

(16) 5- or 6-membered heterocyclyl-carbonyl (preferably,tetrahydropyranylcarbonyl),

(17) carbamoyl,

(18) C₁₋₃ alkylidene optionally substituted by hydroxy, and

(19) imino (═NH) optionally substituted by

-   -   (a) C₁₋₆ alkoxy optionally substituted by hydroxy, or    -   (b) 5- or 6-membered heterocyclyl-oxy (preferably,        tetrahydropyranyloxy), or        [4] a 5- or 6-membered aromatic ring (preferably, phenyl (the        phenyl may form, together with the ring formed by two        substituents, an optionally substituted fused cyclic group or a        spirocyclic group (e.g., 2,3-dihydro-1-benzofuran-5-yl        optionally substituted by C₁₋₆ alkyl)), thienyl) optionally        substituted by 1 to 3 substituents selected from the group        consisting of

(1) a halogen atom,

(2) C₁₋₆ alkyl optionally substituted by hydroxy, and

(3) C₁₋₆ alkoxy optionally substituted by 1 to 3 substituents selectedfrom

-   -   (a) hydroxy, and    -   (b) C₁₋₆ alkyl-carbonyl,        R² is C₁₋₆ alkyl,        W is methylene or —CH(CH₃)—,        A is phenylene, thiophene-di-yl or pyridine-di-yl optionally        substituted by 1 to 3 (preferably 1 or 2) substituents selected        from the group consisting of

(1) a halogen atom, and

(2) C₁₋₆ alkyl optionally substituted by 1 to 3 halogen atoms,

B is a group represented by the formula:

wherein Z⁴ is an oxygen atom or a sulfur atom, or tetrazolyl, andR⁴ is (a) a hydrogen atom, (b) a halogen atom, (c) C₁₋₆ alkyl optionallysubstituted by 1 to 3 substituents selected from the group consisting ofhydroxy, a halogen atom and C₁₋₆ alkoxy or (d) C₃₋₆ cycloalkyl, or asalt thereof.[Compound B4]

A compound represented by the formula:

whereinR¹ is C₃₋₈ cycloalkyl optionally substituted by C₁₋₆ alkoxy optionallysubstituted by1) a halogen atom,2) cyano,3) hydroxy, or4) C₁₋₆ alkoxy optionally substituted by a halogen atom,R² is C₁₋₆ alkyl,A is phenylene optionally substituted by a halogen atom, andR⁴ is a hydrogen atom or methyl, or a salt thereof.[Compound B5]

A compound represented by the formula:

whereinR¹ is cyclohexyl optionally substituted by C₁₋₆ alkoxy optionallysubstituted by hydroxy,R² is C₁₋₆ alkyl, andA is phenylene optionally substituted by a halogen atom, or a saltthereof.[Compound C1]

A compound represented by the formula:

whereinR¹ is a hydrogen atom, optionally substituted C₁₋₆ alkyl, an optionallysubstituted 3- to 10-membered nonaromatic ring or an optionallysubstituted 5- or 6-membered aromatic ring, more preferably, anoptionally substituted 3- to 10-membered nonaromatic ring,R² is optionally substituted C₁₋₆ alkyl,R³ is a hydrogen atom or a halogen atom,W is C₁₋₄ alkylene,A is optionally substituted phenylene, optionally substitutedthiophene-di-yl or optionally substituted pyridine-di-yl,B is a group represented by the formula:

wherein i is —O— or —S—, j is —C(═O)—, —C(═S)— or —S(O)_(m)—, and m isan integer of 0, 1 or 2 (preferably,4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl,4,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl,4,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl), or tetrazolyl, andR⁴ is a hydrogen atom, a halogen atom, optionally substituted C₁₋₆alkyl, optionally substituted C₁₋₆ alkoxy or optionally substituted C₃₋₆cycloalkyl, or a salt thereof.[Compound C2]

A compound represented by the formula:

whereinR¹ is[1] a hydrogen atom,[2] C₁₋₆ alkyl optionally substituted by 1 to 4 substituents selectedfrom the group consisting of

(1) a halogen atom,

(2) hydroxy,

(3) optionally halogenated C₁₋₆ alkoxy,

(4) carboxy optionally substituted by C₁₋₆ alkoxy,

(5) C₁₋₆ alkyl-carbonyl optionally substituted by 1 to 3 halogen atoms,

(6) C₃₋₁₀ cycloalkyl-carbonyl,

(7) C₆₋₁₄ aryl-carbonyl optionally substituted by 1 to 3 halogen atoms,

(8) carbamoyl,

(9) a 3- to 14-membered cyclic group (preferably, cyclopropyl,cyclohexyl, phenyl, pyridyl, oxetanyl, benzimidazolyl (e.g.,benzimidazol-2-yl)) optionally substituted by 1 to 3 substituentsselected from the group consisting of (a) a halogen atom, (b) C₁₋₆ alkyloptionally substituted by hydroxy, (c) C₆₋₁₄ aryl, (d) C₁₋₆ alkoxy and(e) C₁₋₆ alkyl-carbonyl, and

(10) C₁₋₆ alkoxyimino,

[3] a 3- to 10-membered nonaromatic cyclic group (e.g., cyclobutyl,cyclohexyl, cyclohexenyl, tetrahydrofuryl, piperidyl (e.g.,piperidin-4-yl), tetrahydropyranyl, tetrahydrothiopyranyl,tetrahydroindazolyl (e.g., 4,5,6,7-tetrahydroindazol-5-yl), adamantyl,oxepanyl (e.g., oxepan-4-yl)) optionally substituted by 1 to 3substituents selected from the group consisting of

(1) oxo,

(2) hydroxy,

(3) amino optionally substituted by 1 or 2 substituents selected from

-   -   (a) C₁₋₆ alkyl, and    -   (b) a 5- or 6-membered heterocyclic group,

(4) cyano,

(5) C₁₋₆ alkyl optionally substituted by 1 to 3 substituents selectedfrom

-   -   (a) hydroxy,    -   (b) a halogen atom,    -   (c) C₁₋₆ alkoxy, and    -   (d) a 5- or 6-membered heterocyclic group,

(6) C₆₋₁₄ aryl optionally substituted by hydroxy,

(7) C₇₋₁₆ aralkyl,

(8) a heterocyclic group optionally substituted by C₁₋₆ alkyl,

(9) C₁₋₆ alkoxy optionally substituted by 1 to 4 substituents selectedfrom

-   -   (a) a halogen atom,    -   (b) hydroxy,    -   (c) C₃₋₆ cycloalkyl optionally substituted by 1 to 3        substituents selected from the group consisting of C₁₋₆ alkyl        optionally substituted by hydroxy, hydroxy, carbamoyl and cyano,    -   (d) C₁₋₆ alkoxy,    -   (e) cyano,    -   (f) C₁₋₆ alkyl-carbonyl optionally substituted by 1 to 3 halogen        atoms,    -   (g) C₃₋₁₀ cycloalkyl-carbonyl,    -   (h) carbamoyl,    -   (i) C₁₋₆ alkoxyimino,    -   (j) C₁₋₆ alkylthio,    -   (k) C₁₋₆ alkylsulfonyl,    -   (l) C₁₋₆ alkylcarbonyloxy,    -   (m) C₃₋₆ cycloalkyloxy optionally substituted by hydroxy, and    -   (n) a 5- or 6-membered heterocyclic group optionally substituted        by 1 to 3 substituents selected from the group consisting of        C₁₋₆ alkyl and oxo,

(10) C₂₋₆ alkenyloxy optionally substituted by hydroxy,

(11) C₃₋₁₀ cycloalkyloxy optionally substituted by 1 to 3 substituentsselected from the group consisting of

-   -   (a) oxo,    -   (b) hydroxy, and    -   (c) C₁₋₆ alkyl optionally substituted by hydroxy,

(12) C₆₋₁₄ aryloxy optionally substituted by 1 to 3 substituentsselected from

-   -   (a) hydroxy,    -   (b) C₁₋₆ alkyl optionally substituted by hydroxy,    -   (c) C₁₋₆ alkyl-carbonyl, and    -   (d) C₁₋₆ alkoxy,

(13) 5- or 6-membered heterocyclyl-oxy optionally substituted by 1 to 3substituents selected from

-   -   (a) hydroxy, and    -   (b) C₁₋₆ alkyl,

(14) C₁₋₆ alkyl-carbonyloxy optionally substituted by 1 to 3substituents selected from

-   -   (a) hydroxy, and    -   (b) C₁₋₆ alkyl-carbonyloxy,

(15) carboxy optionally substituted by C₁₋₆ alkoxy,

(16) C₁₋₆ alkyl-carbonyl,

(17) C₆₋₁₄ aryl-carbonyl optionally substituted by C₁₋₆ alkoxy,

(18) 5- or 6-membered heterocyclyl-carbonyl,

(19) carbamoyl,

(20) C₁₋₃ alkylidene optionally substituted by hydroxy, and

(21) imino (═NH) optionally substituted by

-   -   (a) C₁₋₆ alkoxy optionally substituted by hydroxy, or    -   (b) 5- or 6-membered heterocyclyl-oxy, or        [4] a 5- or 6-membered aromatic ring (preferably, phenyl,        thienyl) optionally substituted by 1 to 3 substituents selected        from the group consisting of

(1) a halogen atom,

(2) C₁₋₆ alkyl optionally substituted by hydroxy,

(3) C₁₋₆ alkoxy optionally substituted by 1 to 3 substituents selectedfrom

-   -   (a) hydroxy, and    -   (b) C₁₋₆ alkyl-carbonyl, and

(4) C₁₋₆ alkyl-carbonyl,

R² is C₁₋₆ alkyl,

W is C₁₋₄ alkylene,

A is phenylene, thiophene-di-yl or pyridine-di-yl optionally substitutedby 1 to 3 (preferably 1 or 2) substituents selected from

(1) a halogen atom,

(2) nitro,

(3) C₁₋₆ alkyl optionally substituted by 1 to 3 halogen atoms, and

(4) C₁₋₆ alkoxy,

B is a group represented by the formula:

wherein Z⁴ is an oxygen atom or a sulfur atom, or tetrazolyl, andR⁴ is (a) a hydrogen atom, (b) a halogen atom, (c) C₁₋₆ alkyl optionallysubstituted by 1 to 3 substituents selected from the group consisting ofhydroxy, a halogen atom and C₁₋₆ alkoxy or (d) C₃₋₆ cycloalkyl, or asalt thereof.[Compound C3]

A compound represented by the formula:

whereinR¹ is a 3- to 10-membered nonaromatic cyclic group (e.g., cyclohexyl,tetrahydropyranyl) optionally substituted by C₁₋₆ alkoxy (the C₁₋₆alkoxy is optionally substituted by hydroxy), andR² is C₁₋₆ alkyl, or a salt thereof.[Compound D1]

A compound represented by the formula:

whereinR¹ is a hydrogen atom, optionally substituted C₁₋₆ alkyl, an optionallysubstituted 3- to 10-membered nonaromatic ring or an optionallysubstituted 5- or 6-membered aromatic ring,R² is optionally substituted C₁₋₆ alkyl,R³ is a hydrogen atom or a halogen atom,W is C₁₋₄ alkylene,A is optionally substituted phenylene, optionally substitutedthiophene-di-yl or optionally substituted pyridine-di-yl,B is a group represented by the formula:

wherein i is —O— or —S—, j is —C(═O)—, —C(═S)— or —S(O)_(m)—, and m isan integer of 0, 1 or 2 (preferably,4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl,4,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl,4,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl), or tetrazolyl, andR⁴ is a hydrogen atom, a halogen atom, optionally substituted C₁₋₆alkyl, optionally substituted C₁₋₆ alkoxy or optionally substituted C₃₋₆cycloalkyl, or a salt thereof.[Compound D2]

A compound represented by the formula:

whereinR¹ is[1] a hydrogen atom,[2] C₁₋₆ alkyl optionally substituted by 1 to 4 substituents selectedfrom the group consisting of

(1) a halogen atom,

(2) hydroxy,

(3) optionally halogenated C₁₋₆ alkoxy,

(4) carboxy optionally substituted by C₁₋₆ alkoxy,

(5) C₁₋₆ alkyl-carbonyl optionally substituted by 1 to 3 halogen atoms,

(6) C₃₋₁₀ cycloalkyl-carbonyl,

(7) C₆₋₁₄ aryl-carbonyl optionally substituted by 1 to 3 halogen atoms,

(8) carbamoyl,

(9) a 3- to 14-membered cyclic group (preferably, cyclopropyl,cyclohexyl, phenyl, pyridyl, oxetanyl, benzimidazolyl (e.g.,benzimidazol-2-yl)) optionally substituted by 1 to 3 substituentsselected from the group consisting of (a) a halogen atom, (b) C₁₋₆ alkyloptionally substituted by hydroxy, (c) C₆₋₁₄ aryl, (d) C₁₋₆ alkoxy and(e) C₁₋₆ alkyl-carbonyl, and

(10) C₁₋₆ alkoxyimino,

[3] a 3- to 10-membered nonaromatic cyclic group (preferably cyclobutyl,cyclohexyl (the cyclohexyl may form, together with the ring formed bytwo substituents, a spirocyclic group (e.g.,1,4-dioxaspiro[4.5]dec-8-yl)), cyclohexenyl, tetrahydrofuryl, piperidyl(e.g., piperidin-4-yl), tetrahydropyranyl, tetrahydrothiopyranyl,tetrahydroindazolyl (e.g., 4,5,6,7-tetrahydroindazol-5-yl), adamantyl,oxepanyl (e.g., oxepan-4-yl)) optionally substituted by 1 to 3substituents selected from the group consisting of

(1) oxo,

(2) hydroxy,

(3) amino optionally substituted by 1 or 2 substituents selected from

-   -   (a) C₁₋₆ alkyl, and    -   (b) a 5- or 6-membered heterocyclic group,

(4) cyano,

(5) C₁₋₆ alkyl optionally substituted by 1 to 3 substituents selectedfrom

-   -   (a) hydroxy,    -   (b) a halogen atom,    -   (c) C₁₋₆ alkoxy, and    -   (d) a 5- or 6-membered heterocyclic group,

(6) C₆₋₁₄ aryl optionally substituted by hydroxy,

(7) C₇₋₁₆ aralkyl,

(8) a heterocyclic group optionally substituted by C₁₋₆ alkyl,

(9) C₁₋₆ alkoxy optionally substituted by 1 to 4 substituents selectedfrom

-   -   (a) a halogen atom,    -   (b) hydroxy,    -   (c) C₃₋₆ cycloalkyl optionally substituted by 1 to 3        substituents selected from the group consisting of C₁₋₆ alkyl        optionally substituted by hydroxy, hydroxy, carbamoyl and cyano,    -   (d) C₁₋₆ alkoxy,    -   (e) cyano,    -   (f) C₁₋₆ alkyl-carbonyl optionally substituted by 1 to 3 halogen        atoms,    -   (g) C₃₋₁₀ cycloalkyl-carbonyl,    -   (h) carbamoyl,    -   (i) C₁₋₆ alkoxyimino,    -   (j) C₁₋₆ alkylthio,    -   (k) C₁₋₆ alkylsulfonyl,    -   (l) C₁₋₆ alkylcarbonyloxy,    -   (m) C₃₋₆ cycloalkyloxy optionally substituted by hydroxy, and    -   (n) a 5- or 6-membered heterocyclic group optionally substituted        by 1 to 3 substituents selected from the group consisting of        C₁₋₆ alkyl and oxo,

(10) C₂₋₆ alkenyloxy optionally substituted by hydroxy,

(11) C₃₋₁₀ cycloalkyloxy optionally substituted by 1 to 3 substituentsselected from the group consisting of

-   -   (a) oxo,    -   (b) hydroxy, and    -   (c) C₁₋₆ alkyl optionally substituted by hydroxy,

(12) C₆₋₁₄ aryloxy optionally substituted by 1 to 3 substituentsselected from

-   -   (a) hydroxy,    -   (b) C₁₋₆ alkyl optionally substituted by hydroxy,    -   (c) C₁₋₆ alkyl-carbonyl, and    -   (d) C₁₋₆ alkoxy,

(13) 5- or 6-membered heterocyclyl-oxy optionally substituted by 1 to 3substituents selected from

-   -   (a) hydroxy, and    -   (b) C₁₋₆ alkyl,

(14) C₁₋₆ alkyl-carbonyloxy optionally substituted by 1 to 3substituents selected from

-   -   (a) hydroxy, and    -   (b) C₁₋₆ alkyl-carbonyloxy,

(15) carboxy optionally substituted by C₁₋₆ alkoxy,

(16) C₁₋₆ alkyl-carbonyl,

(17) C₆₋₁₄ aryl-carbonyl optionally substituted by C₁₋₆ alkoxy,

(18) 5- or 6-membered heterocyclyl-carbonyl,

(19) carbamoyl,

(20) C₁₋₃ alkylidene optionally substituted by hydroxy, and

(21) imino (═NH) optionally substituted by

-   -   (a) C₁₋₆ alkoxy optionally substituted by hydroxy, or    -   (b) 5- or 6-membered heterocyclyl-oxy, or        [4] a 5- or 6-membered aromatic ring (preferably, phenyl,        thienyl) optionally substituted by 1 to 3 substituents selected        from the group consisting of

(1) a halogen atom,

(2) C₁₋₆ alkyl optionally substituted by hydroxy,

(3) C₁₋₆ alkoxy optionally substituted by 1 to 3 substituents selectedfrom

-   -   (a) hydroxy, and    -   (b) C₁₋₆ alkyl-carbonyl, and

(4) C₁₋₆ alkyl-carbonyl,

R² is C₁₋₆ alkyl,

R³ is a hydrogen atom or a halogen atom,

W is C₁₋₄ alkylene,

A is phenylene, thiophene-di-yl or pyridine-di-yl optionally substitutedby 1 to 3 (preferably 1 or 2) substituents selected from

(1) a halogen atom,

(2) nitro,

(3) C₁₋₆ alkyl optionally substituted by 1 to 3 halogen atoms, and

(4) C₁₋₆ alkoxy,

B is a group represented by the formula:

wherein Z⁴ is an oxygen atom or a sulfur atom, or tetrazolyl, andR⁴ is (a) a hydrogen atom, (b) a halogen atom, (c) C₁₋₆ alkyl optionallysubstituted by 1 to 3 substituents selected from the group consisting ofhydroxy, a halogen atom and C₁₋₆ alkoxy or (d) C₃₋₆ cycloalkyl, or asalt thereof.[Compound D3]

A compound represented by the formula:

whereinR¹ is a 5- or 6-membered aromatic ring (preferably, phenyl) optionallysubstituted by C₁₋₆ alkoxy, andR² is C₁₋₆ alkyl, or a salt thereof.[Compound E]

4-[trans-4-(2-Hydroxy-2-methylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-oneor a salt thereof,6-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-oneor a salt thereof, or(+)-6-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}′-4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-oneand(+)-6-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onemonopotassium salt (1/1) hydrate.

Examples of the salt of a compound represented by the formula (I)include a pharmacologically acceptable salt and the like. Examplesthereof include acid addition salt with an acid such as trifluoroaceticacid, acetic acid, lactic acid, succinic acid, maleic acid, tartaricacid, citric acid, gluconic acid, ascorbic acid, benzoic acid,methanesulfonic acid, p-toluenesulfonic acid, cinnamic acid, fumaricacid, phosphonic acid, hydrochloric acid, nitric acid, hydrobromic acid,hydroiodic acid, sulfamic acid, sulfuric acid and the like; salt with ametal salt such as sodium, potassium, magnesium, calcium and the like;salt with an organic base such as trimethylamine, triethylamine,pyridine, picoline, N-methylpyrrolidine, N-methylpiperidine,N-methylmorpholine and the like, and the like.

A prodrug of a compound represented by the formula (I) or a salt thereof(hereinafter sometimes to be referred to as compound (I)) means acompound which is converted to the compound (I) with a reaction due toan enzyme, an gastric acid, etc. under the physiological condition inthe living body, that is, a compound which is converted to the compound(I) with oxidation, reduction, hydrolysis, etc. according to an enzyme;and a compound which is converted to the compound (I) by hydrolysis etc.due to gastric acid, etc. A prodrug of compound (I) may be a compoundobtained by subjecting an amino group in compound (I) to an acylation,alkylation or phosphorylation (e.g., a compound obtained by subjectingan amino group in compound (I) to an eicosanoylation, alanylation,pentylaminocarbonylation,(5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonylation,tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation ortert-butylation, etc.); a compound obtained by subjecting a hydroxygroup in compound (I) to an acylation, alkylation, phosphorylation orboration (e.g., a compound obtained by subjecting a hydroxy group incompound (I) to an acetylation, palmitoylation, propanoylation,pivaloylation, succinylation, fumarylation, alanylation ordimethylaminomethylcarbonylation, etc.); a compound obtained bysubjecting a carboxyl group in compound (I) to an esterification oramidation (e.g., a compound obtained by subjecting a carboxy group incompound (I) to an ethyl esterification, phenyl esterification,carboxymethyl esterification, dimethylaminomethyl esterification,pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification,phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methylesterification, cyclohexyloxycarbonylethyl esterification ormethylamidation, etc.) and the like. Any of these compounds can beproduced from compound (I) by a method known per se.

A prodrug of the compound (I) may also be one which is converted intothe compound (I) under a physiological condition, such as thosedescribed in IYAKUHIN no KAIHATSU (Development of Pharmaceuticals), Vol.7, Design of Molecules, p. 163-198, 1990, Published by HIROKAWA SHOTEN.

When the compound (I) has isomers such as optical isomer, stereoisomer,positional isomer, rotational isomer and the like, any isomers andmixture of isomers are encompassed in the compound (I). For example,when the compound (I) has an optical isomer, an optical isomer separatedfrom a racemate is also encompassed in the compound (I). These isomerscan be obtained as independent products by a synthesis means or aseparation means (e.g., concentration, solvent extraction, columnchromatography, recrystallization and the like) known per se.

The compound (I) may be a crystal or an amorphous form. When thecompound (I) is a crystal, both a single crystal and crystal mixturesare encompassed in the compound (I). Crystals can be produced bycrystallization according to crystallization methods known per se.

Compound (I) may be a pharmaceutically acceptable cocrystal or acocrystal salt. Here, the cocrystal or cocrystal salt means acrystalline substance, which is constituted from two or more kinds ofspecific solids each having different physical properties (e.g.,structure, melting point, heat of fusion and the like) at roomtemperature. The cocrystal and cocrystal salt can be produced byapplying a cocrystallization method known per se.

The compound (I) may be a solvate (e.g., hydrate etc.) or a non-solvate,both of which are encompassed in the compound (I).

The compound (I) may be labeled with an isotope (e.g., ³H, ¹⁴C, ³⁵S,¹²⁵I and the like) and the like.

Deuterium-converted compound wherein ¹H has been converted to ²H(D) arealso encompassed in the compound (I).

Since compound (I) or a prodrug thereof (hereinafter sometimes to beabbreviated as the compound of the present invention) has a strongangiotensin II antagonistic activity (particularly AT1 receptorantagonistic activity), it is useful as an agent for the prophylaxis ortreatment of a disease in a mammal (e.g., human, monkey, cat, swine,horse, bovine, mouse, rat, guinea pig, dog, rabbit etc.), which isdeveloped (or a disease whose onset is promoted) by coarctation orgrowth of the blood vessel or an organ disorder expressed via anangiotensin II receptor, by the presence of angiotensin II or by afactor induced by the presence of angiotensin II.

Examples of such disease include hypertension, blood pressure circadianrhythm abnormality (e.g., early-morning hypertension, nocturnalhypertension etc.), heart diseases (e.g., cardiac hypertrophy, acuteheart failure, chronic heart failure including cardiac failure, impairedvasodilation, cardiac myopathy, angina pectoris, myocarditis, atrialfibrillation, arrhythmia, tachycardia, myocardial infarction etc.),cerebrovascular disorders (e.g., asymptomatic cerebrovascular disorder,transient cerebral ischemia, cerebral apoplexy, cerebrovasculardementia, hypertensive encephalopathy, cerebral infarction etc.),cerebral edema, cerebral circulatory disorder, recurrence and sequela ofcerebrovascular disorders (e.g., neurotic symptom, psychic symptom,subjective symptom, disorder in daily living activities etc.), ischemicperipheral circulation disorder, myocardial ischemia, venousinsufficiency, progression of cardiac insufficiency after myocardialinfarction, renal diseases (e.g., nephritis, glomerulonephritis,glomerulosclerosis, renal failure, thrombotic vasculopathy, complicationof dialysis, organ dysfunction including nephropathy by radiation damageetc.), arteriosclerosis including atherosclerosis (e.g., aneurysm,coronary sclerosis, cerebral arteriosclerosis, peripheral arterialsclerosis etc.), vascular hypertrophy, vascular hypertrophy orobliteration and organ disorders after intervention (e.g., percutaneoustransluminal coronary angioplasty, stenting, coronary angioscopy,intravascular ultrasound, intracoronary thrombolysis etc.), vascularre-obliteration and restenosis after bypass, polycythemia, hypertension,organ disorder and vascular hypertrophy after transplantation, rejectionafter transplantation, ocular diseases (e.g., glaucoma, ocularhypertension etc.), thrombosis, multiple organ disorder, endothelialdysfunction, hypertensive tinnitus, other cardiovascular diseases (e.g.,deep vein thrombosis, obstructive peripheral circulatory disorder,arteriosclerosis obliterans, thromboangiitis obliterans, ischemiccerebral circulatory disorder, Raynaud's disease, Buerger's diseaseetc.), metabolic and/or nutritional disorders (e.g., obesity,hyperlipemia, hypercholesterolemia, hyperuricacidemia, hyperkalemia,hypernatremia etc.), nerve degeneration diseases (e.g., Alzheimer'sdisease, Parkinson's disease, amyotrophic lateral sclerosis, AIDSencephalopathy etc.), central nervous system disorders (e.g., disorderssuch as cerebral hemorrhage, cerebral infarction etc., and their sequelaand complication, head injury, spinal injury, cerebral edema, sensorymalfunction, sensory functional disorder, autonomic nervous systemdisorder, autonomic nervous system malfunction, multiple sclerosisetc.), dementia (cerebrovascular, senile etc.), defects of memory,disorder of consciousness, amnesia, anxiety symptom, catatonic symptom,discomfort mental state, psychopathies (e.g., depression, epilepsy,alcoholism etc.), inflammatory diseases (e.g., arthritis such asrheumatoid arthritis, osteoarthritis, rheumatoid myelitis, periostitisetc.; inflammation after operation and injury; remission of swelling;pharyngitis; cystitis; pneumonia; atopic dermatitis; inflammatoryintestinal diseases such as Crohn's disease, ulcerative colitis etc.;meningitis; inflammatory ocular disease; pulmonary sarcoidosis such aspneumonia, pulmonary silicosis, pulmonary sarcoidosis, pulmonarytuberculosis etc.), allergic diseases (e.g., allergic rhinitis,conjunctivitis, gastrointestinal allergy, pollinosis, anaphylaxis etc.),chronic obstructive pulmonary disease, interstitial pneumonia,pneumocytis carinni pneumonia, collagen diseases (e.g., systemic lupuserythematosus, scleroderma, polyarteritis etc.), hepatic diseases (e.g.,nonalcoholic fatty hepatic disease or steatohepatitis, hepatitisincluding chronic hepatitis, hepatic cirrhosis etc.), portalhypertension, digestive system disorders (e.g., gastritis, gastriculcer, gastric cancer, gastric disorder after operation, dyspepsia,esophageal ulcer, pancreatitis, colon polyp, cholelithiasis,hemorrhoidal disease, varices ruptures of esophagus and stomach etc.),blood and/or myelopoietic diseases (e.g., erythrocytosis, vascularpurpura, autoimmune hemolytic anemia, disseminated intravascularcoagulation syndrome, multiple myelopathy etc.), bone diseases (e.g.,fracture, refracture, osteoporosis, osteomalacia, bone Paget's disease,sclerosing myelitis, rheumatoid arthritis, osteoarthritis of the kneeand joint tissue dysfunction and the like caused by diseases similar tothese etc.), solid tumor, tumors (e.g., malignant melanoma, malignantlymphoma, cancer of digestive organs (e.g., stomach, intestine etc.)etc.), cancer and cachexia following cancer, metastasis cancer,endocrinopathy (e.g., Addison's disease, Cushing's syndrome,pheochromocytoma, primary aldosteronism etc.), Creutzfeldt-Jakobdisease, urinary organ and/or male genital diseases (e.g., cystitis,prostatic hypertrophy, prostatic cancer, sex infectious disease etc.),female disorders (e.g., climacteric disorder, gestosis, endometriosis,hysteromyoma, ovarian disease, breast disease, sex infectious diseaseetc.), disease relating to environment and occupational factors (e.g.,radiation hazard, hazard by ultraviolet, infrared or laser beam,altitude sickness etc.), sleep apnea syndrome, respiratory diseases(e.g., cold syndrome, pneumonia, asthma, pulmonary hypertension,pulmonary thrombosis and pulmonary embolism etc.), infectious diseases(e.g., viral infectious diseases with cytomegalovirus, influenza virus,herpes virus etc., rickettsiosis, bacterial infectious disease etc.),toxemias (e.g., sepsis, septic shock, endotoxin shock, Gram-negativesepsis, toxic shock syndrome etc.), otorhinolaryngological diseases(e.g., Meniere's syndrome, tinnitus, dysgeusia, vertigo, disequilibrium,dysphagia etc.), skin diseases (e.g., keloid, hemangioma, psoriasisetc.), intradialytic hypotension, myasthenia gravis, systemic diseasessuch as chronic fatigue syndrome and the like.

Since the compound of the present invention can maintain a constanthypotensive activity irrespective of day and night, the dose andfrequency can be reduced as compared to the administration of a compoundother than the compound of the present invention, as well as elevationof blood pressure particularly problematic in patients with hypertensionbefore and after awaking can be suppressed more effectively.

In addition, since the compound of the present invention suppresses theactivity of angiotensin II in a sustained manner for a long time, itimproves or suppresses progression of a disorder or abnormality in thebiological function and physiological activity, which causes variousdiseases associated with adult diseases, aging and the like, and canprimarily and secondarily prevent or suppress progression of a diseaseor pathology caused thereby. Examples of the disorder or abnormality inthe biological function and physiological activity include a disorder orabnormality in the brain circulation or kidney circulationautoregulation, a circulatory disorders (e.g., peripheral, brain,microcirculatory etc.), cerebral blood barrier disorder, sodium chloridesensitivity, coagulation or fibrinolytic system abnormality, abnormalityin the property of blood or blood cell components (e.g., enhancement inplatelet aggregation, abnormality in red blood cell deformability,enhancement in leukocyte adhesiveness, increased blood viscosity etc.),production and promoted activity of growth factor or cytokine (e.g.,PDGF, VEGF, FGF, interleukin, TNF-α, MCP-1 etc.), production andpromoted infiltration of inflammatory system cell, promoted productionof free radical, promotion of fatty deposition, endothelial dysfunction,endothelial, cell and organ disorder, edema, altered morphology of cellin smooth muscle and the like (altered morphology into proliferativeform etc.), production and promoted function of blood vessel vasoactivesubstance or thrombus-induced substance (e.g., catecholamine,endothelin, thromboxane A₂ etc.), abnormal coarctation of blood vesseland the like, abnormal metabolism (e.g., serum lipid abnormality, bloodglucose abnormality etc.), abnormal growth of cells and the like,angiogenesis (including abnormal vasculogenesis in abnormal capillarynet formation of atherosclerosis focal adventitia) and the like.Particularly, the compound of the present invention can be used as aprimary or a secondary agent for the prophylaxis or treatment of organdisorder associated with various diseases (e.g., cardiovasculardisorder, cerebrovascular disorder and organ disorders associatedtherewith, organ disorder associated with circulatory diseases, organdisorder associated with diabetes, organ disorder after interventionetc.). Especially, since the compound of the present invention has aproteinuria suppressive activity, it can be used as a kidney protector.Hence, the compound of the present invention can be advantageously usedeven when patients with insulin resistance, impaired glucose tolerance,diabetes, hyperinsulinemia or obesity have concomitantly developed theabove-mentioned disease or pathology, and can prevent the onset ofhypertension or diabetes in such patients.

The compound of the present invention can be used as insulin sensitizer,agent for enhancing insulin sensitivity, retinoid related receptorfunction regulator, peroxisome proliferator-activated receptor ligand,retinoid X receptor ligand and the like. As used herein, the functionregulator means both agonist and antagonist.

The compound of the present invention has hypoglycemic activity,hypolipidemic activity, insulin resistance improving activity, insulinsensitizing activity and peroxisome proliferator-activated receptor(hereinafter sometimes to be abbreviated as PPAR) γ (GenBank AccessionNo. L40904) agonist activity. As used herein, PPARγ may form aheterodimer receptor with retinoid X receptor (hereinafter sometimes tobe abbreviated as RXR) α (GenBank Accession No. X52773), RXRβ(GenBankAccession No. M84820) or RXRγ (GenBank Accession No. U38480). Thecompound of the present invention has a selective agonist activity onPPARγ.

The compound of the present invention normalizes the intracellularinsulin signal transduction mechanism, which mainly causes insulinresistance, thereby reducing insulin resistance and enhancing insulinactivity, and has a glucose tolerance improvement activity. Therefore,the compound of the present invention can be used for mammals (e.g.,human, monkey, cat, pig, horse, bovine, mouse, rat, guinea pig, dog,rabbit etc.) as an improving agent or an agent for the prophylaxisand/or treatment of the diseases in which insulin resistance isinvolved.

The compound of the present invention can be used as, for example, anagent for the prophylaxis or treatment of diabetes (e.g., type 1diabetes, type 2 diabetes, gestational diabetes, obese diabetes); anagent for the prophylaxis or treatment of hyperlipemia or hyperlipidemia(e.g., hypertriglyceridemia, hypercholesterolemia, hypoHDL-emia,postprandial hyperlipemia); an agent for improving insulin resistance;an insulin sensitizer; an agent for the prophylaxis or treatment ofimpaired glucose tolerance (IGT); or an agent for preventing progressionof hypertension, impaired glucose tolerance or obesity to diabetes. Inaddition, the compound of the present invention can be used as, forexample, an agent for the prophylaxis or treatment of hyperinsulinemiaor hypertension associated with insulin resistance, hypertensionassociated with impaired glucose tolerance, hypertension associated withdiabetes (e.g., type II diabetes etc.), hypertension associated withhyperinsulinemia, hypertension associated with obesity, insulinresistance occurring in association with hypertension, impaired glucosetolerance occurring in association with hypertension, diabetes occurringin association with hypertension, hyperinsulinemia occurring inassociation with hypertension, or obesity occurring in association withhypertension. Moreover, the compound of the present invention can alsobe used for the treatment of patients with high normal blood pressurewho has developed diabetes.

The compound of the present invention can also be used as an agent forthe prophylaxis or treatment of, for example, diabetic complications[e.g., neuropathy, nephropathy, retinopathy, cataract, macroangiopathy,osteopenia, hyperosmolar diabetic coma, infections (e.g., respiratoryinfection, urinary tract infection, gastrointestinal infection, dermalsoft tissue infections, inferior limb infection), diabetic gangrene,xerostomia hypacusis, hypacusis, cerebrovascular disorder, peripheralblood circulation disorder], obesity and obesity complication, sleepapnea syndrome, osteoporosis, cachexia (e.g., carcinomatous cachexia,tuberculous cachexia, diabetic cachexia, hemopathic cachexia,endocrinopathic cachexia, infectious cachexia or cachexia induced byacquired immunodeficiency syndrome), fatty liver, nonalcoholicsteatohepatitis, hypertension, polycystic ovary syndrome, renal diseases(e.g., diabetic nephropathy, glomerulonephritis, glomerulosclerosis,nephrosis syndrome, hypertensive nephrosclerosis, end-stage renaldisorder), muscular dystrophy, myocardial infarction, angina pectoris,cardiac failure, cerebrovascular disorders (e.g., cerebral infarction,cerebral apoplexy), insulin resistance syndrome, syndrome X, metabolicsyndrome (pathology having 3 or more selected fromhyper-triglycerid(TG)emia, low HDL cholesteremia (HDL-C), hypertension,abdomen obesity and impaired glucose tolerance), hyperinsulinemia,perception disorder in hyperinsulinemia, tumor (e.g., leukemia, breastcancer, prostate cancer, skin cancer), irritable bowel syndrome, acuteor chronic diarrhea, inflammatory diseases (e.g., arteriosclerosis(e.g., atherosclerosis etc.), rheumatoid arthritis, spondylitisdeformans, osteoarthritis, lumbago, gout, hyperuricemia, post-surgicalor posttraumatic inflammation, swelling, neuralgia, pharyngolaryngitis,cystitis, hepatitis (including nonalcoholic steatohepatitis), pneumonia,pancreatitis, inflammatory colitis, ulcerative colitis), visceralobesity syndrome and the like.

The compound of the present invention can be used for the improvement ofsymptoms such as abdominal pain, nausea, vomiting, epigastric discomfortand the like associated with peptic ulcer, acute or chronic gastritis,biliary dyskinesia, cholecystitis or the like.

The compound of the present invention can also be used as an agent forthe prophylaxis or treatment of inflammatory diseases involving TNF-α.Here, the inflammatory diseases involving TNF-α is an inflammatorydisease developed by the presence of TNF-α and treated via a TNF-αsuppressive effect. Examples of the inflammatory disease includediabetic complications (e.g., retinopathy, nephropathy, neuropathy,macroangiopathy), myocarditis, cardiomyopathy, cardiac failure, ischemiccardiac diseases, rheumatoid arthritis, spondylitis deformans,osteoarthritis, lumbago, gout, post-surgical or posttraumaticinflammation, swelling, neuralgia, pharyngolaryngitis, cystitis,hepatitis, pneumonia, gastric mucosa injury (including gastric mucosainjury caused by aspirin) and the like.

The compound of the present invention has an apoptosis suppressiveactivity and is also used as an agent for the prophylaxis or treatmentof diseases involving promoted apoptosis. Here, examples of the diseaseinvolving promoted apoptosis include virus diseases (e.g., AIDS,fulminant hepatitis), neurodegenerative diseases (e.g., Alzheimer'sdisease, Parkinson's disease, amyotrophic lateral sclerosis, pigmentosa,cerebellar degeneration), myelodysplasia (e.g., aplastic anemia),ischemic diseases (e.g., myocardial infarction, cerebral apoplexy),hepatic diseases (e.g., nonalcoholic steatohepatitis, alcoholichepatitis, Hepatitis B, Hepatitis C), articular diseases (e.g.,osteoarthritis), atherosclerosis and the like.

The compound of the present invention can be used for reducing visceralfats, inhibiting accumulation of visceral fats, amelioratingglycometabolism, ameliorating lipid metabolism, ameliorating insulinresistance, inhibiting oxidized LDL production, ameliorating lipoproteinmetabolism, ameliorating coronary artery metabolism, preventing ortreating cardiovascular complications, preventing or treating heartfailure complications, lowering blood remnant, preventing or treatinganovulation, preventing or treating hirsutism, preventing or treatinghyperandrogenism, and the like.

The compound of the present invention is also used for the secondaryprevention of various diseases mentioned above (e.g., cardiovascularevent such as myocardial infarction etc.) and suppression of progressionthereof.

For diagnostic criteria of diabetes, Japan Diabetes Society reporteddiagnostic criteria in 1999.

According to this report, diabetes is a condition showing any of afasting blood glucose level (glucose concentration of intravenousplasma) of not less than 126 mg/dl, a 75 g oral glucose tolerance test(75 g OGTT) 2 h level (glucose concentration of intravenous plasma) ofnot less than 200 mg/dl, and a non-fasting blood glucose level (glucoseconcentration of intravenous plasma) of not less than 200 mg/dl. Acondition not falling under the above-mentioned diabetes and differentfrom “a condition showing a fasting blood glucose level (glucoseconcentration of intravenous plasma) of less than 110 mg/dl or a 75 goral glucose tolerance test (75 g OGTT) 2 h level (glucose concentrationof intravenous plasma) of less than 140 mg/dl” (normal type) is called a“borderline type”.

In addition, ADA (American Diabetes Association) reported diagnosticcriteria of diabetes in 1997 and WHO in 1998.

According to these reports, diabetes is a condition showing a fastingblood glucose level (glucose concentration of intravenous plasma) of notless than 126 mg/dl and a 75 g oral glucose tolerance test 2 h level(glucose concentration of intravenous plasma) of not less than 200mg/dl.

According to the above-mentioned reports, impaired glucose tolerance isa condition showing a fasting blood glucose level (glucose concentrationof intravenous plasma) of less than 126 mg/dl and a 75 g oral glucosetolerance test 2 h level (glucose concentration of intravenous plasma)of not less than 140 mg/dl and less than 200 mg/dl. According to thereport of ADA, a condition showing a fasting blood glucose level(glucose concentration of intravenous plasma) of not less than 110 mg/dland less than 126 mg/dl is called IFG (Impaired Fasting Glucose).According to the report of WHO, among the IFG (Impaired FastingGlucose), a condition showing a 75 g oral glucose tolerance test 2 hlevel (glucose concentration of intravenous plasma) of less than 140mg/dl is called IFG (Impaired Fasting Glycemia).

The compound of the present invention can also be used as an agent forimproving or the prophylaxis or treatment of diabetes, borderline type,impaired glucose tolerance, IFG (Impaired Fasting Glucose) and IFG(Impaired Fasting Glycemia), as determined according to theabove-mentioned diagnostic criteria, or further, as an agent fortreating hypertension of hypertensive patients having not less than theabove-mentioned diagnostic criteria (e.g., fasting blood sugar level of126 mg/dl). Moreover, the compound of the present invention can preventprogression of borderline type, impaired glucose tolerance, IFG(Impaired Fasting Glucose) or IFG (Impaired Fasting Glycemia) intodiabetes.

The compound of the present invention is effective as an agent for thesuppression or improvement of cardiac hypofunction, progression ofcardiac remodeling and aggravation of conditions in, or an agent for thesuppression of decreased survival rate of, cardiac patients (e.g.,cardiac hypertrophy, acute cardiac failure, chronic cardiac failureincluding congestive cardiac failure, impaired vasodilation,cardiomyopathy, angina pectoris, myocarditis, atrial fibrillation,arrhythmia, tachycardia, myocardial infarction and the like) withdiabetes. In addition, it is effective for the prevention of the onsetof cardiac diseases (e.g., cardiac hypertrophy, acute cardiac failure,chronic cardiac failure including congestive cardiac failure, impairedvasodilation, cardiomyopathy, angina pectoris, myocarditis, atrialfibrillation, arrhythmia, tachycardia, myocardial infarction and thelike) and cerebrovascular disorders (e.g., asymptomatic cerebrovasculardisorder, transient cerebral ischemic attack, cerebral apoplexy,cerebrovascular dementia, hypertensive encephalopathia, cerebralinfarction and the like) in diabetic patients.

Since the compound of the present invention has an activity ofinhibiting body weight gain, it can be used as a body weight gaininhibitor to mammals. Target mammals may be any mammals of which bodyweight gain is to be avoided. The mammals may have a risk of body weightgain genetically or may be suffering from lifestyle-related diseasessuch as diabetes, hypertension and/or hyperlipidemia etc. The bodyweight gain may be caused by excessive feeding or diet without nutrientbalance, or may be derived from combination agent, for example, agentsfor enhancing insulin sensitivity having PPARγ-agonistic activity suchas troglitazone, rosiglitazone, englitazone, ciglitazone, pioglitazoneetc. and the like. In addition, body weight gain may be preliminary toobesity, or may be body weight gain of obesity patients. Here, obesityis defined that BMI (body mass index; body weight (kg)/[height (m)]²) isat least twenty-five for Japanese (criterion by Japan Society for theStudy of Obesity), or at least thirty for westerner (criterion by WHO).

The compound of the present invention is useful as an agent for theprophylaxis or treatment of metabolic syndrome. Since patients withmetabolic syndrome have an extreme high incidence of cardiovasculardiseases as compared to patients with single lifestyle-related diseases,the prophylaxis or treatment of metabolic syndrome is quite important toprevent cardiovascular diseases.

Criteria for diagnosis of metabolic syndrome are announced by WHO in1999, and by NCEP in 2001. According to the criterion of WHO, patientswith at least two of abdominal obesity, dyslipidemia (high TG or lowHDL) and hypertension in addition to hyperinsulinemia or impairedglucose tolerance are diagnosed as metabolic syndrome (World HealthOrganization: Definition, Diagnosis and Classification of DiabetesMellitus and Its Complications. Part I: Diagnosis and Classification ofDiabetes Mellitus, World Health Organization, Geneva, 1999). Accordingto the criterion of Adult Treatment Panel III of National CholesterolEducation Program, that is an indicator for managing ischemic heartdiseases in the United States, patients with at least three of abdominalobesity, hypertriglyceridemia, hypo-HDL cholesterolemia, hypertensionand impaired glucose tolerance are diagnosed as metabolic syndrome(National Cholesterol Education Program: Executive Summary of the ThirdReport of National Cholesterol Education Program (NCEP) Expert Panel onDetection, Evaluation, and Treatment of High Blood Cholesterol in Adults(Adults Treatment Panel III). The Journal of the American MedicalAssociation, Vol. 285, 2486-2497, 2001).

The compound of the present invention can be used for treating patientsof hypertension with metabolic syndrome.

Since the compound of the present invention has an anti-inflammatoryactivity, it can be used as an anti-inflammatory agent for preventing ortreating inflammatory diseases. Examples of the inflammatory diseasesinclude inflammatory diseases due to various diseases such as arthritis(e.g. rheumatoid arthritis, osteoarthritis, rheumatoid myelitis, goutyarthritis, synovitis), asthma, allergic diseases, arteriosclerosisincluding atherosclerosis (aneurysm, coronary sclerosis, cerebralarterial sclerosis, peripheral arterial sclerosis etc.), digestive tractdiseases such as inflammatory intestine disease (e.g. Crohn's disease,ulcerative colitis), diabetic complications (diabetic neuropathy,diabetic vascular disorder), atopic dermatitis, chronic obstructivepulmonary disease, systemic lupus erythematosus, visceral inflammatorydiseases (nephritic, hepatitis, nonalcoholic steatohepatitis etc.),autoimmune hemolytic anemia, psoriasis, nervous degenerative diseases(e.g. Alzheimer's disease, Parkinson's diseases, amyotrophic lateralsclerosis, AIDS encephalopathy), central nervous disorders (e.g.cerebrovascular disorders such as cerebral hemorrhage, cerebral infarctetc., head trauma, spinal damage, cerebral edema, multiple sclerosisetc.), meningitis, angina pectoris, cardiac infarct, congestive cardiacfailure, vascular hypertrophy or occlusion and organ disorder afterintervention (percutaneous transluminal coronary angioplasty, stenting,coronary angioscopy, intravascular ultrasound, intracoronarythrombolysis etc.), vascular reocclusion or restenosis after bypassoperation, endothelial functional disorder, other circulatory diseases(intermittent claudication, obstructive peripheral circulatory disorder,arteriosclerosis obliterans, thromboangiitis obliterans, ischemiccerebral circulatory disorder, Raynaud's disease, Buerger's diseaseetc.), inflammatory ocular disease, inflammatory pulmonary diseases(e.g. chronic pneumonia, silicosis, pulmonary sarcoidosis, pulmonarytuberculosis), endometritis, toxemia (e.g. sepsis, septic shock,endotoxin shock, gram negative sepsis, toxin shock syndrome), cachexia(e.g. cachexia due to infection, carcinomatous cachexia, cachexia due toacquired immunodeficiency syndrome), cancer, Addison's disease,Creutzfeldt-Jakob disease, virus infection (e.g. infection of virus suchas cytomegalovirus, influenza virus, herpes virus etc.), disseminatedintravascular coagulation and the like.

In addition, since the compound of the present invention has ananalgesic activity, it can be also used as an analgesic agent forpreventing or treating pain. Examples of the pain disease include acutepain due to inflammation, pains associated with chronic inflammation,pain associated with acute inflammation, pain after operation(incisional pain, deep pain, organ pain, chronic pain after operationetc.), muscular pains (muscular pain associated with chronic paindisease, shoulder stiffness etc.), arthralgia, toothache,gnathicarthralgia, headaches (migraine, stress headache, catatonicheadache, headache associated with fever, headache associatedhypertension), organ pains (cardiac pain, angina pain, abdominal pain,renal pain, ureterane pain, bladder pain), pains in obstetrics area(mittelschmerz, dysmenorrheal, labor pain), neuralgia (disc hernia,nerve root pain, neuralgia after herpes zoster, trigeminal neuralgia),carcinomatous pain, reflex sympathetic atrophy, complex local painsyndrome, and the like. The compound of the present invention iseffective for alleviating directly and rapidly various pains such asnervous pain, carcinomatous pain, inflammatory pain etc., and exhibitsthe particularly excellent analgesic effect to patients and pathologies(e.g., hypertension, diabetes etc., and complications thereof etc.) inwhich a pain sense threshold is lowered.

The compound of the present invention is particularly useful as ananalgesic agent for pain associated with chronic inflammation or painassociated with hypertension, or as an agent for preventing or treatinginflammatory disease or pain due to (1) arteriosclerosis includingatherosclerosis, (2) vascular hypertrophy, occlusion or organ disorderafter intervention, (3) reocclusion, restenosis or endothelialfunctional disorder after bypass operation, (4) intermittentclaudication, (5) obstructive peripheral circulatory disorder, or (6)arteriosclerosis obliterans.

The content of the compound of the present invention in a medicament isgenerally about 0.01-about 99.9 wt %, preferably about 0.1-about 50 wt%, relative to the entire preparation.

The dose of the compound of the present invention is determined inconsideration of age, body weight, general health condition, sex, diet,administration time, administration method, clearance rate, combinationof agents, the level of disease for which the patient is under treatmentthen, and other factors.

While the dose varies depending on the target disease, symptom, subjectof administration, administration method and the like, for oraladministration as a therapeutic agent for adult essential hypertension,for example, it is generally about 0.01-100 mg/kg body weight,preferably 0.05-30 mg/kg body weight, more preferably 0.5-10 mg/kg bodyweight, as one dose, which is preferably administered once to 3 times aday.

In addition, since the compound of the present invention shows lowtoxicity and superior safety, it can be administered for a long period.

As the medicament of the present invention, the compound of the presentinvention can be administered orally or parenterally as it is or afteradmixing with a pharmacologically acceptable carrier.

As the medicament of the present invention comprising compound (I), thecompound of the present invention can be safely administered alone or ismixed with a pharmacologically acceptable carrier according to a methodknown per se as a production method of a pharmaceutical preparation(e.g., the method described in the Japanese Pharmacopoeia etc.) andadministered as, for example, tablet (including sugar-coated tablet,film-coated tablet, sublingual tablet, orally disintegrating tablet,buccal tablet and the like), pill, powder, granule, capsule (includingsoft capsule, microcapsule), troche, syrup, liquid, emulsion,suspension, controlled-release preparation (e.g., immediate-releasepreparation, sustained-release preparation, sustained-releasemicrocapsule), aerosol, film (e.g., orally disintegrable film, oralmucous membrane patch film), injection (e.g., subcutaneous injection,intravenous injection, intramuscular injection, intraperitonealinjection), drip infusion, transdermal absorption type preparation,ointment, lotion, adhesive preparation, suppository (e.g., rectalsuppository, vaginal suppository), pellet, nasal preparation, pulmonarypreparation (inhalant), eye drop etc., orally or parenterally (e.g.,intravenous, intramuscular, subcutaneous, intraorgan, intranasal,intradermal, instillation, intracerebral, rectal, vaginal,intraperitoneal and intratumor administrations, administration to thevicinity of tumor etc. and direct administration to the lesion).

When the compound of the present invention is to be produced in theabove-mentioned dosage form, it can be produced by adding as necessaryan appropriate amount of excipient, binder, disintegrant, lubricant,sweetening agent, surfactant, suspending agent, emulsifier and the like,which are generally used in the pharmaceutical field, during productionof the dosage form.

For example, when the compound of the present invention is to beproduced as a tablet, it can be produced by adding excipient, binder,disintegrant, lubricant and the like, when it is to be produced as pillor granule, it can be produced by adding excipient, binder, disintegrantand the like. When the compound of the present invention is to beproduced as powder or capsule, it can be produced by adding excipientand the like, when it is to be produced as syrup, it can be produced byadding sweetening agent and the like, and when it is to be produced asemulsion or suspension, it can be produced by adding suspending agent,surfactant, emulsifier and the like.

Examples of the excipient include lactose, sucrose, glucose, starch,saccharose, crystalline cellulose, powdered glycyrrhiza, mannitol,sodium hydrogen carbonate, calcium phosphate, calcium sulfate and thelike.

Examples of the binder include 5-10 wt % starch liquid paste, 10-20 wt %gum arabic solution or gelatin solution, 1-5 wt % tragacanth solution,carboxymethyl cellulose solution, sodium alginate solution, glycerin andthe like.

Examples of the disintegrant include starch, calcium carbonate and thelike.

Examples of the lubricant include magnesium stearate, stearic acid,calcium stearate, purified talc and the like.

Examples of the sweetener include glucose, fructose, invert sugar,sorbitol, xylitol, glycerin, simple syrup and the like.

Examples of the surfactant include sodium lauryl sulfate, polysorbate80, sorbitan monofatty acid ester, polyoxyl 40 stearate and the like.

Examples of the suspending agent include gum arabic, sodium alginate,sodium carboxymethyl cellulose, methyl cellulose, bentonite and thelike.

Examples of the emulsifier include gum arabic, tragacanth, gelatin,polysorbate 80 and the like.

Furthermore, when the compound of the present invention is produced inthe above-mentioned dosage form, a suitable amount of a colorant, apreservative, an aromatic, a corrigent, a stabilizer, a thickening agentand the like typically used in the field of preparation can be added ondemand.

When the compound of the present invention is administered parenterally,it is generally administered in the form of a liquid formulation (e.g.,injection). While the dose varies depending on the subject ofadministration, target organ, symptom, administration method and thelike, it is, for example, about 0.01 mg to about 100 mg, preferablyabout 0.01 to about 50 mg, more preferably about 0.01 to about 20 mg, inthe form of an injection, relative to 1 kg of body weight, which ispreferably given by intravenous injection. As the injection, intravenousinjection as well as subcutaneous injection, intracutaneous injection,intramuscular injection, instillation and the like are mentioned, and asa sustained release preparation, iontophoresis transdermal agent and thelike are mentioned. Such injections are prepared by methods known perse, i.e., by dissolving, suspending or emulsifying the compound (I) in asterilized aqueous solution or oily liquid. As an aqueous solution forinjection, physiological saline, isotonic solutions comprising glucoseor other auxiliary agents (e.g., D-sorbitol, D-mannitol, sodium chlorideand the like) and the like can be mentioned, and they can be used incombination with suitable solubilizing agents, such as alcohols (e.g.,ethanol), polyalcohols (e.g., propylene glycol, polyethylene glycol),nonionic surfactants (e.g., polysorbate 80, HCO-50) and the like. As anoily liquid, sesame oil, soybean oil and the like can be mentioned,which may be used in combination with solubilizing agents such as benzylbenzoate, benzyl alcohol and the like. In addition, buffers (e.g.,phosphate buffer, sodium acetate buffer), soothing agents (e.g.,benzalkonium chloride, procaine hydrochloride and the like), stabilizers(e.g., human serum albumin, polyethylene glycol and the like),preservatives (e.g., benzyl alcohol, phenol and the like) and the likemay be mixed therewith. A prepared injection is generally filled in anampoule.

The compound of the present invention can be used in combination withmedicaments such as a therapeutic agent for diabetes, a therapeuticagent for diabetic complications, an anti-hyperlipidemia agent, ananti-arteriosclerotic agent, an anti-hypertensive agent, an antiobesticagent, a diuretic, an antigout agent, an antithrombotic agent, ananti-inflammatory agent, a chemotherapeutic agent, an immunotherapeuticagent, a therapeutic agent for osteoporosis, an anti-dementia agent, anerectile dysfunction amelioration agent, a therapeutic agent for urinaryincontinence/urinary frequency, a therapeutic agent for dysurea and thelike (hereinafter to be abbreviated as a concomitant agent). Theseconcomitant agents may be low-molecular-weight compounds,high-molecular-weight proteins, polypeptides, antibodies, vaccines andthe like.

Examples of the therapeutic agents for diabetes include insulinpreparations (e.g., animal insulin preparations extracted from pancreasof bovine and swine; human insulin preparations genetically synthesizedusing Escherichia coli, yeast; zinc insulin; protamine zinc insulin;fragment or derivative of insulin (e.g., INS-1), oral insulinpreparation), insulin sensitizers (e.g., pioglitazone or a salt thereof(preferably hydrochloride), rosiglitazone or a salt thereof (preferablymaleate), Netoglitazone (MCC-555), Rivoglitazone (CS-011), FK-614, acompound described in WO01/38325, Tesaglitazar (AZ-242), Ragaglitazar(N,N-622), Muraglitazar (BMS-298585), Edaglitazone (BM-13-1258),Metaglidasen (MBX-102), Naveglitazar (LY-519818), MX-6054, LY-510929,AMG131 (T-131) or a salt thereof, THR-0921), α-glucosidase inhibitors(e.g., voglibose, acarbose, miglitol, emiglitate), biguanides (e.g.,phenformin, metformin, buformin or a salt thereof (e.g., hydrochloride,fumarate, succinate)), insulin secretagogues [sulfonylureas (e.g.,tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide,acetohexamide, glyclopyramide, glimepiride, glipizide, glybuzole),repaglinide, nateglinide, mitiglinide or a calcium salt hydratethereof], dipeptidyl peptidase IV inhibitors (e.g., Vildagliptin(LAF237), P32/98, Sitagliptin (MK-431), alogliptin, P93/01, PT-100,Saxagliptin (BMS-477118), BI1356, GRC8200, MP-513, PF-00734200, PHX1149,SK-0403, ALS2-0426, TA-6666, TS-021, KRP-104,2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-4-fluorobenzonitrileor a salt thereof), β3 agonists (e.g., AJ-9677), GPR40 agonists, GLP-1receptor agonists [e.g., GLP-1, GLP-1MR agent, N,N-2211, AC-2993(exendin-4), BIM-51077, Aib(8,35)hGLP-1(7,37)NH₂, CJC-1131], amylinagonists (e.g., pramlintide), phosphotyrosine phosphatase inhibitors(e.g., sodium vanadate), gluconeogenesis inhibitors (e.g., glycogenphosphorylase inhibitors, glucose-6-phosphatase inhibitors, glucagonantagonists), SGLUT (sodium-glucose cotransporter) inhibitors (e.g.,T-1095, dapagliflozin, remogliflozin), 11β-hydroxysteroid dehydrogenaseinhibitors (e.g., BVT-3498), adiponectin or agonists thereof, IKKinhibitors (e.g., AS-2868), leptin resistance improving drugs,somatostatin receptor agonists (compounds etc. described in WO01/25228,WO03/42204, WO98/44921, WO98/45285, WO99/22735), glucokinase activators(e.g., Ro-28-1675), ACC2 (acetyl-CoA carboxylase 2) inhibitor and thelike.

Examples of the therapeutic agents for diabetic complications includealdose reductase inhibitors (e.g., tolrestat, epalrestat, zenarestat,zopolrestat, minalrestat, fidarestat, CT-112, ranirestat (AS-3201)),neurotrophic factors and enhancers thereof (e.g., NGF, NT-3, BDNF,neurotrophin production/secretion promoting agents described inWO01/14372 (e.g.,4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole)),PKC inhibitors (e.g., ruboxistaurin mesylate), AGE inhibitors (e.g.,ALT946, pimagedine, N-phenacylthiazolium bromide (ALT766), EXO-226,Pyridorin, pyridoxamine), active oxygen scavengers (e.g., thiocticacid), cerebral vasodilators (e.g., tiapride, mexiletine), somatostatinreceptor agonists (e.g., BIM23190), apoptosis signal regulating kinase-1(ASK-1) inhibitors and the like.

Examples of the anti-hyperlipidemia agents include statin compoundswhich are cholesterol synthesis inhibitors (e.g., cerivastatin,pravastatin, simvastatin, lovastatin, rosuvastatin, atorvastatin,fluvastatin, pitavastatin or salts thereof (e.g., sodium salt etc.)etc.), squalene synthetase inhibitors or fibrate compounds having atriglyceride lowering effect (e.g., bezafibrate, clofibrate, simfibrate,clinofibrate etc.), cholesterol absorption inhibitors (e.g., zechia),anion exchange resins (e.g., colestyramine), probucol, nicotinic aciddrugs (e.g., nicomol, niceritrol), phytosterols (e.g., soysterol,γ-oryzanol), fish oil preparations (EPA, DHA, Omacor etc.) PPARαagonists, PPARγ agonists, PPARδ agonists, LXR agonists, FXR antagonists,FXR agonists, DGAT inhibitors, MGAT inhibitors, MTP inhibitors (e.g.,lomitapide), nucleic acid medicaments containing ApoB antisense (e.g.,mipomersen) or PCSK9 siRNA antisense oligonucleotide, and the like.

Examples of the anti-arteriosclerotic agent include Lp-PLA2 inhibitors(e.g., darapladib, rilapladib etc.), FLAP inhibitors (e.g., AM-103,AM-803, DG-031 etc.), sPLA2 inhibitors (e.g., varespladib),5-lipoxygenase inhibitors (e.g., VIA-2291 etc.), acyl coenzyme Acholesterol acyltransferase (ACAT) inhibitors (e.g., melinamide,Avasimibe, Eflucimibe etc.), lipid-rich plaque regressing agents (e.g.,compounds described in WO02/06264, WO03/059900 etc.), HDL preparations(e.g., CSL-111 etc.), CTEP inhibitors (e.g., torcetrapib, anacetrapib,dalcetrapib etc.), MMP inhibitors, chymase inhibitors, SPT inhibitors,ApoA-1 and related molecules thereof (e.g., ApoA-1 Milano, D-4F, L-4Fetc.) and the like.

Examples of the anti-hypertensive agents include angiotensin convertingenzyme inhibitors (e.g., captopril, enalapril, delapril etc.),angiotensin II antagonists (e.g., candesartan cilexetil, candesartan,azilsartan, azilsartan medoxomil, losartan, losartan potassium,eprosartan, valsartan, termisartan, irbesartan, tasosartan, olmesartan,olmesartan medoxomil etc.), calcium antagonists (e.g., manidipine,nifedipine, amlodipine, efonidipine, nicardipine etc.), β-blockers(e.g., propranolol, nadolol, timolol, nipradilol, bunitrolol, indenolol,Penbutolol, carteolol, carvedilol, pindolol, acebutolol, atenolol,bisoprolol, metoprolol, labetalol, amosulalol, arotinolol etc.),clonidine and the like. Examples of the antiobestic agent includemonoamine uptake inhibitors (e.g., phentermine, sibutramine, mazindol,fluoxetine, tesofensine), serotonin 2C receptor agonists (e.g.,lorcaserin), serotonin 6 receptor antagonists, histamine H3 receptors,GABA-modulating agents (e.g., topiramate), neuropeptide γ antagonists(e.g., velneperit), cannabinoid receptor antagonists (e.g., rimonabant,taranabant), ghrelin antagonists, ghrelin receptor antagonists, ghrelinacylation enzyme inhibitors, opioid receptor antagonists (e.g.,GSK-1521498), orexin receptor antagonists, melanocortin 4 receptoragonists, 11β-hydroxysteroid dehydrogenase inhibitors (e.g., AZD-4017),pancreatic lipase inhibitors (e.g., orlistat, cetilistat), β3 agonists(e.g., N-5984), diacylglycerol acyltransferase 1 (DGAT1) inhibitors,acetyl CoA carboxylase (ACC) inhibitors, stearic acid CoA desaturationenzyme inhibitors, microsomal triglyceride transfer protein inhibitors(e.g., R-256918), Na-glucose cotransport carrier inhibitor (e.g.,JNJ-28431754, remogliflozin), NFK inhibitors (e.g., HE-3286), PPARagonists (e.g., GFT-505, DRF-11605), phosphotyrosine phosphataseinhibitors (e.g., sodium vanadate, Trodusquemin), GPR119 agonists (e.g.,PSN-821), glucokinase activators (e.g., AZD-1656), leptin, leptinderivatives (e.g., metreleptin), CNTF (ciliary neurotrophic factor),BDNF (brain-derived neurotrophic factor), cholecystokinin agonists,glucagon-like peptide-1 (GLP-1) preparations (e.g., animal GLP-1preparation extracted from pancreas of bovine and swine; human GLP-1preparations genetically synthesized using Escherichia coli, yeast;fragment or derivative of GLP-1 (e.g., exenatide, liraglutide)), amylinpreparations (e.g., pramlintide, AC-2307), neuropeptide γ agonists(e.g., PYY3-36, derivative of PYY3-36, obinepitide, TM-30339, TM-30335),oxyntomodulin preparations: FGF21 preparations (e.g., animal FGF21preparation extracted from pancreas of bovine and swine; human FGF21preparations genetically synthesized using Escherichia coli, yeast;fragment or derivative of FGF21)), feeding deterrents (e.g., P-57) andthe like.

Examples of the diuretics include xanthine derivatives (e.g.,theobromine sodium salicylate, theobromine calcium salicylate etc.),thiazide preparations (e.g., ethiazide, cyclopenthiazide,trichloromethiazide, hydrochlorothiazide, hydroflumethiazide,benzylhydrochlorothiazide, penfluthiazide, poly5 thiazide,methyclothiazide etc.), antialdosterone preparations (e.g.,spironolactone, eplerenone, triamterene etc.), carbonate dehydrataseinhibitors (e.g., acetazolamide etc.), chlorobenzenesulfonamidepreparations (e.g., chlortalidone, mefruside, indapamide etc.),azosemide, isosorbide, etacrynic acid, piretanide, bumetanide,furosemide and the like.

Examples of anti-hyperuricemic or antigout agents include allopurinol,probenecid, colchicine, benzbromarone, febuxostat, citrate and the like.

Examples of the antithrombotic agent include anticoagulants [e.g.,heparin sodium, heparin calcium, warfarin calcium (warfarin),anti-thrombin drugs (e.g., aragatroban, dabigatran), activated bloodcoagulation factor Xa inhibitors (e.g., rivaroxaban, apixaban, edoxaban,YM-150, compounds described in WO02/06234, WO2004/048363, WO2005/030740,WO2005/058823, WO2005/113504 and WO2004/048363 etc.) etc.], thrombolyticagents [e.g., tPA, urokinase, tisokinase, alteplase, nateplase,monteplase, pamiteplase], antiplatelet agents [e.g., aspirin,sulfinpyrazone (anturan), dipyridamole (persantin), ticlopidine(panaldine), cilostazol (pletal), GPIIb/IIIa antagonists (e.g., reoproetc.), clopidogrel, prasugrel, ticagrelor, E5555, SHC530348, ethylicosapentate, beraprost sodium, sarpogrelate hydrochloride etc.] and thelike.

Examples of the anti-inflammatory agents include non-steroidalanti-inflammatory agents such as acetaminophen, fenasetin, ethenzamide,sulpyrine, antipyrine, migrenin, aspirin, mefenamic acid, flufenamicacid, diclofenac sodium, loxoprofen sodium, phenylbutazone,indomethacin, ibuprofen, ketoprofen, naproxen, oxaprozin, flurbiprofen,fenbufen, pranoprofen, floctafenine, epirizol, tiaramide hydrochloride,zaltoprofen, gabexate mesylate, camostat mesylate, ulinastatin,colchicine, probenecid, sulfinpyrazone, benzbromarone, allopurinol,sodium gold thiomalate, sodium hyaluronate, sodium salicylate, morphinehydrochloride, salicylic acid, atropine, scopolamine, morphine,pethidine, levorphanol, ketoprofen, naproxen, oxymorphone and saltsthereof etc., and the like.

Examples of the chemotherapeutic agents include alkylating agents (e.g.,cyclophosphamide, ifosfamide etc.), metabolic antagonists (e.g.,methotrexate, 5-fluorouracil etc.), antitumor antibiotics (e.g.,mitomycin, adriamycin etc.), plant-derived antitumor agents (e.g.,vincristine, vindesine, Taxol etc.), cisplatin, carboplatin, etoposideand the like. Of these, Furtulon or NeoFurtulon, which are5-fluorouracil derivatives, and the like are preferable.

Examples of the immunotherapeutic agents include microorganism orbacterial components (e.g., muramyl dipeptide derivative, Picibaniletc.), polysaccharides having immunity potentiating activity (e.g.,lentinan, schizophyllan, krestin etc.), cytokines obtained by geneticengineering techniques (e.g., interferon, interleukin (IL) etc.), colonystimulating factors (e.g., granulocyte colony stimulating factor,erythropoietin etc.) and the like, with preference given to IL-1, IL-2,IL-12 and the like.

Examples of the therapeutic agents for osteoporosis includealfacalcidol, calcitriol, elcatonin, calcitonin salmon, estriol,ipriflavone, pamidronate disodium, alendronate sodium hydrate,incadronate disodium and the like.

Examples of the anti-dementia agents include tacrine, donepezil,rivastigmine, galanthamine and the like.

Examples of the erectile dysfunction amelioration agents includeapomorphine, sildenafil citrate and the like.

Examples of the therapeutic agents for urinary incontinence/urinaryfrequency include flavoxate hydrochloride, oxybutynin hydrochloride,propiverine hydrochloride and the like.

Examples of the therapeutic agents for dysuria include acetylcholineesterase inhibitors (e.g., distigmine) and the like.

Furthermore, drugs having a cachexia-improving activity established inanimal models and clinical situations, such as cyclooxygenase inhibitors(e.g., indomethacin etc.) [Cancer Research, Vol. 49, pages 5935-5939,1989], progesterone derivatives (e.g., megestrol acetate) [Journal ofClinical Oncology, Vol. 12, pages 213-225, 1994], glucosteroids (e.g.,dexamethasone etc.), metoclopramide agents, tetrahydrocannabinol agents(publications are all as mentioned above), fat metabolism improvingagents (e.g., eicosapentanoic acid etc.) [British Journal of Cancer,Vol. 68, pages 314-318, 1993], growth hormones, IGF-1, or antibodies toa cachexia-inducing factor such as TNF-α, LIF, IL-6, oncostatin M andthe like, can be used in combination with the compound of the presentinvention.

Furthermore, examples of the concomitant agent include nerveregeneration promoting drugs (e.g., Y-128, VX853, prosaptide),antidepressants (e.g., desipramine, amitriptyline, imipramine),antiepileptics (e.g., lamotrigine), antiarrhythmic agents (e.g.,mexiletine), acetylcholine receptor ligands (e.g., ABT-594), endothelinreceptor antagonists (e.g., ABT-627), monoamine uptake inhibitors (e.g.,tramadol), narcotic analgesics (e.g., morphine), GABA receptor agonists(e.g., gabapentin), α2 receptor agonists (e.g., clonidine), localanalgesics (e.g., capsaicin), antianxiety drugs (e.g., benzodiazepines),dopamine agonists (e.g., apomorphine), midazolam, ketoconazole and thelike.

The combination agent preferably includes calcium antagonist,aldosterone receptor antagonist, diuretic, insulin preparation, insulinsensitizer, dipeptidyl peptidase IV inhibitor, α-glucosidase inhibitor,biguanide agent, insulin secretagogue (preferably sulfonylurea agent)and the like. Particularly, calcium antagonists such as amlodipine andthe like, aldosterone receptor antagonists such as eplerenone and thelike, diuretic such as hydrochlorothiazide, chlortalidone and the like,insulin sensitizers such as pioglitazone hydrochloride and the like, andtherapeutic agents for diabetes such as alogliptin, metformin and thelike are preferable.

The timing of administration of the aforementioned combination agent isnot limited, and the compound of the present invention and a combinationagent may be simultaneously administered to the subject ofadministration, or may be administered with time difference. The dose ofthe combination agent may be according to the clinical dose, and can bedetermined appropriately according to the subject of administration,administration route, disease, combination and the like.

The above-mentioned combination agent may be a combination of two ormore kinds thereof combined at appropriate ratios. In this case, thetiming of administration of the compound of the present invention and acombination agent is not limited, and the compound of the presentinvention and a combination agent only need to be combined at the timeof administration.

Examples of such administration mode include the following:

(1) administration of a single preparation obtained by simultaneouslyprocessing the compound of the present invention and the concomitantagent, (2) simultaneous administration of two kinds of preparations ofthe compound of the present invention and the concomitant agent, whichhave been separately produced, by the same administration route, (3)administration of two kinds of preparations of the compound of thepresent invention and the concomitant agent, which have been separatelyproduced, by the same administration route in a staggered manner, (4)simultaneous administration of two kinds of preparations of the compoundof the present invention and the concomitant agent, which have beenseparately produced, by different administration routes, (5)administration of two kinds of preparations of the compound of thepresent invention and the concomitant agent, which have been separatelyproduced, by different administration routes in a staggered manner(e.g., administration in the order of the compound of the presentinvention and the concomitant agent, or in the reverse order) and thelike. The dose of the concomitant agent can be appropriately determinedbased on the dose clinically employed. The mixing ratio of the compoundof the present invention and the concomitant agent can be appropriatelyselected according to the administration subject, administration route,target disease, condition, combination, and other factors. In caseswhere the administration subject is human, for example, the concomitantagent may be used in an amount of 0.01 to 100 parts by weight per partby weight of the compound of the present invention.

When the compound of the present invention is used in combination with aconcomitant agent, the amount of each drug can be reduced within a saferange in consideration of the opposite effect of these drugs.Particularly, the dose of the insulin sensitizer, insulin secretagogueand biguanide can be reduced from conventional level. As a result, theside effects possibly caused by these agents can be prevented safely. Inaddition, the dose of the therapeutic agent for diabetic complications,anti-hyperlipidemia agent or anti-hypertensive agent can be reduced and,as a result, the side effects possibly caused by these drugs can beeffectively prevented.

Since the compound of the present invention potentiates hypoglycemicactivity of other insulin sensitizers, a combined use of the compound ofthe present invention and other insulin sensitizers (preferablypioglitazone hydrochloride) markedly enhances a prophylactic and/ortherapeutic effect against diseases in which insulin resistance isinvolved, such as type II diabetes and the like.

Production Method

The production method of compound (I) is explained below.

Compound (I) can be produced, for example, by the method shown in thefollowing or a method analogous thereto and the like. In the followingsynthesis method, respective starting material compounds may form a saltas long as it does not inhibit the reaction. As such salt, thoseexemplified as a salt of the aforementioned compound represented byformula (I) are used. The starting material compounds may becommercially available when a specific production method is notdescribed, or can be produced according to a method known per se or amethod analogous thereto.

While the yield of compound (I) obtained by each of the followingmethods may vary depending on the reaction conditions used, compound (I)can be obtained easily at a high purity from the resultant products by aconventional separation and purification means (e.g., recrystallization,column chromatography and the like).

wherein X, Y, Z, R¹, R², R³, W and A are as defined above.

In reaction (a), compound (Ib) [compound (I) wherein B is

is obtained from compound (Ia) [compound (I) wherein B is

obtained by the below-mentioned reaction (g) or (h) in the presence ofan aqueous alkaline solution. This reaction is generally performed usingabout 1-3 mol of an aqueous alkali solution per 1 mol of compound (1a)in a solvent inert to the reaction.

Examples of the inert solvent for reaction include ethers such as1,4-dioxane, tetrahydrofuran and the like; alcohols such as methanol,ethanol and the like; water and the like. These solvents may be used asa mixture of two or more kinds thereof at an appropriate ratio.

Examples of the alkali include sodium hydroxide, potassium hydroxide,lithium hydroxide, sodium carbonate, potassium carbonate and the like.

The reaction temperature is generally about −50° C. to about 150° C.,preferably about 0° C. to about 60° C.

The reaction time is generally about 0.5 to about 20 hr.

wherein X, Y, Z, R¹, R², R³, W and A are as defined above.

In reaction (b), compound (II) obtained in the below-mentioned reaction(d), (f), (i) or (j) is converted to compound (III), and subjected toring-closure to give compound (Ib).

The reaction for obtaining compound (III) from compound (II) isperformed using about 1-20 mol of hydroxylamine per 1 mol of compound(II) in an organic solvent inert to the reaction.

Examples of the organic solvent inert to the reaction include amidessuch as N,N-dimethylformamide, N,N-dimethylacetamide and the like;alcohols such as methanol, ethanol and the like; ethers such as1,4-dioxane, tetrahydrofuran and the like; sulfoxides such as dimethylsulfoxide and the like, and the like. These solvents may be used in amixture of two or more kinds thereof at an appropriate ratio.

Examples of hydroxylamine include inorganic acid salts such ashydroxylamine hydrochloride, hydroxylamine hydrosulphate and the like,organic acid salts such as hydroxylamine oxalate etc., and the like.When the inorganic acid salt or organic acid salt of hydroxylamine isused, the reaction is preferably performed in the co-presence of anequivalent or small excess of a suitable base such as potassiumcarbonate, sodium hydrogen carbonate, sodium hydroxide, triethylamine,sodium methoxide, sodium hydride and the like. When an inorganic acidsalt or organic acid salt of hydroxylamine is used, the reaction may beperformed using about 5-20% of water in the organic solvent.

The reaction temperature is generally about −50° C. to about 150° C.,preferably about 25° C. to about 100° C.

The reaction time is generally about 3 to about 48 hr.

The reaction to obtain compound (Ib) from compound (III) is performedusing about 1-2 mol of a carbonylation reagent per 1 mol of compound(III) in the presence of an equivalent amount or small excess of a basein a solvent that does not adversely influence the reaction.

Examples of the carbonylation reagent include N,N′-carbonyldiimidazole,triphosgene, methyl chlorocarbonate, ethyl chlorocarbonate and the like.

Examples of the base include organic amines such as triethylamine,pyridine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene andthe like; inorganic salts such as potassium carbonate, sodium carbonateetc., and the like.

Examples of the solvent that does not adversely influence the reactioninclude halogenated carbons such as dichloromethane, chloroform, carbontetrachloride and the like; amides such as N,N-dimethylformamide,N,N-dimethylacetamide and the like; ethers such as diethyl ether,1,4-dioxane, tetrahydrofuran etc., and the like. These solvents may beused in a mixture of two or more kinds thereof at an appropriate ratio.

The reaction temperature is generally about −50° C. to about 100° C.,preferably about 0° C. to about 50° C.

The reaction time is generally about 0.1 to about 5 hr.

wherein X, Y, Z, R¹, R², R³, W and A are as defined above.

In reaction (c), compound (III) obtained in the aforementioned reaction(b) is subjected to ring-closure to give compound (Ic) [compound (I)wherein B is

This reaction is performed using about 1-2 mol of1,1-thiocarbonyldiimidazole per 1 mol of compound (III) in the presenceof Lewis acid in an organic solvent that does not adversely influencethe reaction.

The Lewis acid is not particularly limited as long as the reactionproceeds and, for example, boron trifluoride-diethyl ether complex,tin(II) chloride, zinc chloride, copper(I) chloride and the like can bementioned. The amount of the Lewis acids is preferably about 1 to 3 molper 1 mol of compound (III).

Examples of the organic solvent that does not adversely influence thereaction include halogenated carbons such as dichloromethane,chloroform, carbon tetrachloride and the like; amides such asN,N-dimethylformamide, N,N-dimethylacetamide and the like; dimethylsulfoxide and the like; ethers such as diethyl ether, 1,4-dioxane,tetrahydrofuran and the like and the like. These solvents may be used ina mixture of two or more kinds thereof at an appropriate ratio.

The reaction temperature is generally about −50° C. to about 100° C.,preferably about 0° C. to about 50° C.

The reaction time is generally about 0.1 to about 5 hr.

wherein X, Y, Z, R¹, R², R³, W and A are as defined above, and R¹³ is analkyl group (e.g., methyl, ethyl, tert-butyl).

In reaction (d), compound (II), which is the starting material compoundof the aforementioned reaction (b), is obtained by a condensationreaction of compound (IV) obtained by the below-mentioned reaction (e)and compound (V). This reaction is generally performed using about 1-10mol of compound (V) per 1 mol of compound (IV) without a solvent or inan organic solvent that does not adversely influence the reaction. Thisreaction may be performed in the presence of a base.

Examples of the organic solvent that does not adversely influence thereaction include amides such as N,N-dimethylformamide,N,N-dimethylacetamide and the like; alcohols such as methanol, ethanoland the like; ethers such as 1,4-dioxane, tetrahydrofuran and the like;aromatic hydrocarbons such as benzene, toluene, trichlorobenzene and thelike; and anilines such as aniline, N,N-diethylaniline and the like.These solvents may be used in a mixture of two or more kinds thereof atan appropriate ratio.

The base is not particularly limited as long as the reaction proceeds,and examples thereof include alkali metal salts such as potassiumhydroxide, sodium hydroxide, sodium hydrogen carbonate, potassiumcarbonate and the like; amines such as pyridine, triethylamine,N,N-dimethylaniline, 1,8-diazabicyclo[5.4.0]undec-7-ene and the like;metal hydrides such as potassium hydride, sodium hydride and the like;and alkali metal alkoxides such as sodium methoxide, sodium ethoxide,potassium tert-butoxide and the like.

The reaction temperature is generally about −50° C. to about 300° C.,preferably about 25° C. to about 200° C.

The reaction time is generally about 1 to about 48 hr.

The above-mentioned reaction may be performed using a microwavesynthesis apparatus. In this case, the reaction temperature is generallyabout −50° C. to about 300° C., preferably about 100° C. to about 250°C. The reaction time is generally about 15 min to about 12 hr.

Compound (V), which is the starting material compound of this reaction,can be produced according to a method known per se, for example, themethod described in Journal of Medicinal Chemistry vol. 37, page 2371(1994) or the method described in WO2008/062905, or a method analogousthereto.

wherein X, Y, Z and R¹ are as defined above.

In reaction (e), compound (IV), which is the starting material compoundof the aforementioned reaction (d), is obtained by a reductive aminationreaction of compound (VI) and compound (VII). This reaction is performedaccording to a method known per se, for example, the method described inJournal of Organic Chemistry vol. 61, page 3849 (1996) and the like, ora method analogous thereto, and is generally performed using about 1-10mol of compound (VII) and about 1-10 mol of a suitable reducing agentper 1 mol of compound (VI) in a solvent inert to the reaction.

Examples of the inert solvent for the reaction include halogenatedhydrocarbons such as chloroform, dichloromethane and the like; etherssuch as 1,4-dioxane, tetrahydrofuran and the like; alcohols such asmethanol, ethanol and the like; water, acetic acid and the like. Thesesolvents may be used in a mixture of two or more kinds thereof at anappropriate ratio.

Examples of the reducing agent include formic acid, sodium borohydride,sodium triacetoxyborohydride, sodium cyanoborohydride and the like.

The reaction temperature is generally about −50° C. to about 150° C.,preferably about 0° C. to about 60° C.

The reaction time is generally about 0.5 to about 20 hr.

Compound (VI), which is the starting material compound of this reaction,can be produced according to a method known per se, for example, themethod described in Bioorganic and Medicinal Chemistry Letters vol. 17,page 6220 (2007) or a method analogous thereto.

wherein X, Y, Z, R¹, R², R³, W and A are as defined above, and E¹ is aleaving group (e.g., halogen atoms such as chlorine, bromine, iodineetc., substituted sulfonic acid esters such as methanesulfonic acidester, p-toluenesulfonic acid ester, trifluoromethanesulfonic acid esteretc., boronic acid or boronic acid ester, hydroxy etc.).

In Reaction (f), compound (VIII) is reacted with compound (IX) toproduce compound (II), which is the starting material compound of theaforementioned reaction (b). This reaction is generally performed using1-4 mol of compound (IX) per 1 mol of compound (VIII).

Compound (VIII), which is the starting material compound of thisreaction, can be produced according to a method analogous to theproduction method shown in the aforementioned reaction (d).

When E¹ is a halogen atom or substituted sulfonic acid ester, thereaction is performed according to a conventional method in the presenceof a base in a solvent that does not adversely influence the reaction.

Examples of the base include alkali metal salts such as potassiumhydroxide, sodium hydroxide, sodium hydrogen carbonate, potassiumcarbonate and the like; amines such as pyridine, triethylamine,N,N-dimethylaniline, 1,8-diazabicyclo[5.4.0]undec-7-ene and the like;metal hydrides such as potassium hydride, sodium hydride and the like;alkali metal alkoxides such as sodium methoxide, sodium ethoxide andpotassium tert-butoxide, and the like.

The amount of these bases to be used is preferably about 1-about 5 molper 1 mol of compound (VIII).

Examples of the solvent that does not adversely influence the reactioninclude aromatic hydrocarbons such as benzene, toluene, xylene and thelike; nitriles such as acetonitrile, propionitrile and the like; etherssuch as tetrahydrofuran, 1,4-dioxane, diethyl ether and the like;ketones such as acetone, 2-butanone and the like; halogenatedhydrocarbons such as chloroform, dichloromethane and the like; amidessuch as N,N-dimethylformamide and the like; sulfoxides such as dimethylsulfoxide etc., and the like. These solvents may be used in a mixture oftwo or more kinds thereof at an appropriate ratio.

The reaction temperature is generally about −50° C. to about 150° C.,preferably about −10° C. to about 100° C.

The reaction time is generally about 0.5 to about 20 hr.

When E¹ is hydroxy, this reaction is performed according to a methodknown per se, for example, the method described in Synthesis, p. 1(1981) and the like or a method analogous thereto. That is, thisreaction is generally performed in the presence of an organic phosphoruscompound and an azo reagent in a solvent that does not adverselyinfluence the reaction.

Examples of the organic phosphorus compound include triphenylphosphine,tri(n-butyl)phosphine and the like.

Examples of the azo reagent include diethyl azodicarboxylate,diisopropyl azodicarboxylate, azodicarbonyl dipiperazine and the like.

The amount of the organic phosphorous compound or azo reagent to be usedis preferably about 1-about 5 mol per 1 mol of compound (VIII).

Examples of the solvent that does not adversely influence the reactioninclude ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane andthe like; halogenated hydrocarbons such as chloroform, dichloromethaneand the like; aromatic hydrocarbons such as benzene, toluene, xylene andthe like; amides such as N,N-dimethylformamide and the like; sulfoxidessuch as dimethyl sulfoxide etc., and the like. These solvents may beused in a mixture of two or more kinds thereof at an appropriate ratio.

The reaction temperature is generally about −50° C. to about 150° C.,preferably about −10° C. to about 100° C.

The reaction time is generally about 0.5 to about 20 hr.

Particularly, when E¹ is a halogen atom or substituted sulfonic acidester, and R¹ is a 5- or 6-membered aromatic cyclic group, this reactioncan be promoted according to a method known per se, for example, themethod described in Journal of the American Chemical Society vol. 124,page 7421 (2002) and the like, or a method analogous thereto, in thepresence of a metal catalyst. Examples of the metal catalyst includepalladium complex (e.g., palladium acetate, palladium chloride,tetrakis(triphenylphosphine)palladium,dichlorobis(triphenylphosphine)palladium,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium etc.), coppercompounds (e.g., copper powder, copper(I) chloride, copper(I) iodide,copper(I) acetate etc.), nickel compounds (e.g.,tetrakis(triphenylphosphine)nickel etc.), rhodium compounds (e.g.,tris(triphenylphosphine)rhodium chloride etc.), platinum compounds andthe like.

The amount of these metal catalysts to be used is about 0.000001 mol-5mol, preferably 0.0001 mol-1 mol, per 1 mol of compound (VIII).

The above-mentioned reaction may be performed in the presence of a baseand/or a ligand. Examples of the base include metal alkoxides such aspotassium phenoxide, sodium tert-butoxide and the like; inorganic saltssuch as potassium carbonate, sodium carbonate, cesium carbonate,potassium phosphate and the like, and the like. Examples of the ligandinclude organic phosphorus compounds such as triphenylphosphine,tri-tert-butylphosphine, tri-cyclohexylphosphine, BINAP(2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) and the like; organicamine compounds such as N,N′-dimethyl-cyclohexane-1,2-diamine,2,2-bipyridyl and the like, and the like.

When a metal catalyst unstable to oxygen is used, this reaction ispreferably performed under an inert gas (e.g., argon, nitrogen etc.)atmosphere.

The reaction temperature is generally about −50° C. to about 150° C.,preferably about −10° C. to about 100° C.

The reaction time is generally about 0.5 to about 20 hr.

When E¹ is a boronic acid or a boronic acid ester, this reaction isperformed according to a method known per se, for example, the methoddescribed in Tetrahedron Letters, vol. 39, p. 2933 (1998) and the likeor a method analogous thereto, in the presence of a base and a metalcatalyst, in a solvent that does not adversely influence the reaction.

Examples of the base include inorganic salts such as potassiumcarbonate, sodium carbonate, cesium carbonate and the like; metalalkoxides such as sodium methoxide, sodium ethoxide, potassiumtert-butoxide and the like; amines such as pyridine, triethylamine,N,N-dimethylaniline, 1,8-diazabicyclo[5,4,0]undec-7-ene etc., and thelike. These bases may be used in a mixture of two or more kinds thereofat an appropriate ratio.

Examples of the metal catalyst include copper or salts thereof (e.g.,copper(II) acetate, copper(II) chloride and the like), palladiumcomplexes (e.g., palladium acetate, palladium chloride,tetrakis(triphenylphosphine)palladium,dichlorobis(triphenylphosphine)palladium,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium and the like),nickel compounds (e.g., tetrakis(triphenylphosphine)nickel and thelike), rhodium compounds (tris(triphenylphosphine)rhodium chloride andthe like), platinum compounds and the like. Of these, copper and saltsthereof are preferable.

Examples of the solvent that does not adversely influence the reactioninclude aromatic hydrocarbons such as benzene, toluene, xylene and thelike; ethers such as tetrahydrofuran, 1,4-dioxane, diethyl ether and thelike; ketones such as acetone, 2-butanone and the like; halogenatedhydrocarbons such as chloroform, dichloromethane and the like; amidessuch as N,N-dimethylformamide and the like; sulfoxides such as dimethylsulfoxide etc., and the like. These solvents may be used in a mixture oftwo or more kinds thereof at an appropriate ratio.

When copper or a salt thereof is used as a metal catalyst, this reactionis preferably performed under an air atmosphere or an oxygen atmosphere.When a metal catalyst unstable to oxygen is used, this reaction ispreferably performed under an inert gas (e.g., argon, nitrogen and thelike) atmosphere. In addition, this reaction may be performed usingmolecular sieves.

The amount of the metal catalyst to be used is about 0.000001 mol-5 mol,preferably 0.0001 mol-1 mol, per 1 mol of compound (VIII).

The reaction temperature is generally about 0° C. to about 200° C.,preferably 10° C. to about 100° C.

The reaction time is generally about 1 to about 96 hr.

wherein X, Y, Z, R¹, R², R³, B, W and A are as defined above, and R⁵ andR⁶ are each a leaving group (e.g., halogen atoms such as chlorine,bromine, iodine etc.; substituted sulfonic acid esters such asmethanesulfonic acid ester, p-toluenesulfonic acid ester,trifluoromethane sulfonic acid ester etc.; hydroxy group etc.) or ametal (e.g., potassium, sodium, lithium, magnesium, copper, mercury,zinc, thallium, boron, tin etc.).

In reaction (g), compound (X) is reacted with compound (XI) to givecompound (I).

This reaction is performed using about 1-3 mol of compound (XI) per 1mol of compound (X) in an organic solvent that does not adverselyinfluence the reaction.

Examples of the organic solvent that does not adversely influence thereaction include alcohols such as methanol, ethanol, ethylene glycol andthe like; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane andthe like; halogenated hydrocarbons such as chloroform, dichloromethaneand the like; aromatic hydrocarbons such as benzene, toluene, xylene andthe like; amides such as N,N-dimethylformamide and the like; sulfoxidessuch as dimethyl sulfoxide and the like and the like. These solvents maybe used in a mixture of two or more kinds thereof at an appropriateratio. Furthermore, water may be added at an appropriate ratio.

Compound (X), which is the starting material compound of this reaction,can be produced according to a method analogous to the production methodshown in the aforementioned reaction (d) or reaction (f).

When R⁵ is a leaving group (e.g., halogen atoms such as chlorine,bromine, iodine and the like; substituted sulfonic acid esters such astrifluoromethane sulfonic acid ester and the like etc.), and R⁶ is ametal (e.g., potassium, sodium, lithium, magnesium, copper, mercury,zinc, thallium, boron, tin etc.), this reaction can be promoted byperforming the reaction in the presence of metal catalyst according to amethod known per se, for example, the method described in Journal of theAmerican Chemical Society vol. 124, page 7421 (2002) and the like, or amethod analogous thereto. Examples of the metal catalyst includepalladium compounds (e.g., palladium acetate, palladium chloride,tetrakis(triphenylphosphine)palladium,dichlorobis(triphenylphosphine)palladium,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium etc.), coppercompounds (e.g., copper powder, copper(I) chloride, copper(I) iodide,copper(I) acetate etc.), nickel compounds (e.g.,tetrakis(triphenylphosphine)nickel etc.), rhodium compounds (e.g.,tris(triphenylphosphine)rhodium chloride etc.), platinum compounds andthe like.

The amount of the metal catalyst to be used is about 0.000001 mol-5 mol,preferably 0.0001 mol-1 mol, per 1 mol of compound (X).

The above-mentioned reaction may be performed in the presence of a baseand/or a ligand. Examples of the base include metal alkoxides such aspotassium phenoxide, sodium tert-butoxide and the like; inorganic saltssuch as potassium carbonate, sodium carbonate, cesium carbonate,potassium phosphate and the like and the like. Examples of the ligandinclude organic phosphorus compounds such as triphenylphosphine,tri-tert-butylphosphine, tri-cyclohexylphosphine, BINAP(2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) and the like; organicamine compounds such as N,N′-dimethyl-cyclohexane-1,2-diamine,2,2-bipyridyl and the like, and the like.

When a metal catalyst unstable to oxygen is used, this reaction ispreferably performed under an inert gas (e.g., argon, nitrogen etc.)atmosphere.

The reaction temperature is generally about −50° C. to about 150° C.,preferably about −10° C. to about 120° C.

The reaction time is generally about 0.5-about 20 hr.

When R⁵ is a metal (e.g., potassium, sodium, lithium, magnesium, copper,mercury, zinc, thallium, boron, tin etc.), and R⁶ is a leaving group(e.g., halogen atoms such as chlorine, bromine, iodine etc.; substitutedsulfonic acid esters such as trifluoromethanesulfonic acid ester etc.,and the like), this reaction can be promoted by performing the reactionin the presence of a metal catalyst according to a method known per se,for example, the method described in Journal of the American ChemicalSociety vol. 124, page 7421 (2002) and the like, or a method analogousthereto. Examples of the metal catalyst include palladium compounds(e.g., palladium acetate, palladium chloride,tetrakis(triphenylphosphine)palladium,dichlorobis(triphenylphosphine)palladium,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium etc.), coppercompounds (e.g., copper powder, copper(I) chloride, copper(I) iodide,copper(I) acetate etc.), nickel compounds (e.g.,tetrakis(triphenylphosphine)nickel etc.), rhodium compounds (e.g.,tris(triphenylphosphine)rhodium chloride etc.), platinum compounds andthe like.

The amount of the metal catalyst to be used is about 0.000001 mol-5 mol,preferably 0.0001 mol-1 mol, per 1 mol of compound (X).

The above-mentioned reaction may be performed in the presence of a baseand/or a ligand. Examples of the base include metal alkoxides such aspotassium phenoxide, sodium tert-butoxide and the like; inorganic saltssuch as potassium carbonate, sodium carbonate, cesium carbonate,potassium phosphate etc., and the like. Examples of the ligand includeorganic phosphorus compounds such as triphenylphosphine,tri-tert-butylphosphine, tri-cyclohexylphosphine, BINAP(2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) and the like; organicamine compounds such as N,N′-dimethyl-cyclohexane-1,2-diamine,2,2-bipyridyl etc., and the like.

When a metal catalyst unstable to oxygen is used, this reaction ispreferably performed under an inert gas (e.g., argon, nitrogen etc.)atmosphere.

The reaction temperature is generally about −50° C. to about 150° C.,preferably about −10° C. to about 120° C.

The reaction time is generally about 0.5 to about 20 hr.

wherein X, Y, Z, R¹, R², R³, R⁵, R⁶, W, A and B are as defined above.

In reaction (h), compound (XII) is reacted with compound (XIII) to givecompound (I).

When R⁵ is a leaving group (e.g., halogen atoms such as chlorine,bromine, iodine etc.; substituted sulfonic acid esters such astrifluoromethanesulfonic acid ester etc., and the like), and R⁶ is ametal (e.g., potassium, sodium, lithium, magnesium, copper, mercury,zinc, thallium, boron, tin etc.), this reaction can be performed in thesame manner as in reaction (g).

When R⁵ is a metal (e.g., potassium, sodium, lithium, magnesium, copper,mercury, zinc, thallium, boron, tin etc.), and R⁶ is a leaving group(e.g., halogen atoms such as chlorine, bromine, iodine etc.; substitutedsulfonic acid esters such as trifluoromethanesulfonic acid ester etc.,and the like), this reaction can be performed in the same manner as inreaction (g)

Compound (XII), which is the starting material compound of thisreaction, can be produced according to a method analogous to theproduction method shown in the aforementioned reaction (d) or reaction(f).

wherein X, Y, Z, R¹, R², R², R⁵, R⁶, W and A are as defined above.

In reaction (i), compound (XII) is reacted with compound (XIV) to givecompound (II).

When R⁵ is a leaving group (e.g., halogen atoms such as chlorine,bromine, iodine etc.; substituted sulfonic acid esters such astrifluoromethanesulfonic acid ester etc., and the like), and R⁶ is ametal (e.g., potassium, sodium, lithium, magnesium, copper, mercury,zinc, thallium, boron, tin etc.), this reaction can be performed in thesame manner as in reaction (g).

When R⁵ is a metal (e.g., potassium, sodium, lithium, magnesium, copper,mercury, zinc, thallium, boron, tin etc.), and R⁶ is a leaving group(e.g., halogen atoms such as chlorine, bromine, iodine etc.; substitutedsulfonic acid esters such as trifluoromethanesulfonic acid ester etc.,and the like), this reaction can be performed in the same manner as inreaction (g).

wherein X, Y, Z, R¹, R², R³, W and A are as defined above, E² is aleaving group (e.g., halogen atoms such as chlorine, bromine, iodineetc., and the like; substituted sulfonic acid esters such astrifluoromethanesulfonic acid ester etc., and the like), and M is ametal (e.g., copper, zinc, tin etc.)

In reaction (j), compound (XV) is reacted with compound (XVI) to givecompound (II). The amount of compound (XVI) to be used is preferablyabout 1-about 5 mol, per 1 mol of compound (XV).

This reaction is performed in a solvent that does not adverselyinfluence the reaction. Preferable examples of the solvent that does notadversely influence the reaction include solvents such as alcohols(e.g., methanol, ethanol, ethylene glycol etc.), ethers (e.g., diethylether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane etc.), amides(e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidoneetc.), aromatic hydrocarbons (e.g., toluene, xylene etc.) and the like.These solvents may be used in a mixture of two or more kinds thereof atan appropriate ratio. Furthermore, water may be added at an appropriateratio.

This reaction can be promoted by performing according to a method knownper se, for example, the method described in Tetrahedron Letters vol.40, page 8193 (1999) and the like, or a method analogous thereto, in thepresence of a metal catalyst. Examples of the metal catalyst includepalladium compounds (e.g., palladium acetate, palladium chloride,tetrakis(triphenylphosphine)palladium,dichlorobis(triphenylphosphine)palladium,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium etc.), coppercompounds (e.g., copper powder, copper(I) chloride, copper(I) iodide,copper(I) acetate etc.), nickel compounds (e.g.,tetrakis(triphenylphosphine)nickel etc.), rhodium compounds (e.g.,tris(triphenylphosphine)rhodium chloride etc.), platinum compounds andthe like.

The amount of the metal catalyst to be used is about 0.000001 mol-5 mol,preferably 0.0001 mol-1 mol, per 1 mol of compound (XV).

This reaction may be performed in the presence of a ligand. Examples ofthe ligand include organic phosphorus compounds such astriphenylphosphine, tri-tert-butylphosphine, tri-cyclohexylphosphine,BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) and the like;organic amine compounds such as N,N′-dimethyl-cyclohexane-1,2-diamine,2,2-bipyridyl etc., and the like.

When a metal catalyst unstable to oxygen is used, this reaction ispreferably performed under an inert gas (e.g., argon, nitrogen etc.)atmosphere.

The reaction temperature is generally about −50° C. to about 300° C.,preferably about −10° C. to about 150° C.

The reaction time is generally about 0.5-about 20 hr.

Compound (XV), which is the starting material compound of this reaction,can be produced according to a method analogous to the production methodshown in the aforementioned reaction (d) or reaction (f).

wherein X, Y, Z, W, A, R² and R³ are as defined above, R⁷ is optionallysubstituted C₁₋₆ alkylene (e.g., methylene, ethylene, propylene etc.),an optionally substituted 3- to 10-membered nonaromatic cyclic group oran optionally substituted 5- or 6-membered aromatic cyclic group, R⁸ isoptionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₁₀cycloalkyl, optionally substituted C₆₋₁₄ aryl or optionally substitutedC₇₋₁₆ aralkyl, E³ is a leaving group (e.g., halogen atoms such aschlorine, bromine, iodine etc.; substituted sulfonic acid esters such asmethanesulfonic acid ester, p-toluenesulfonic acid ester,trifluoromethanesulfonic acid ester etc.), or hydroxy, and E⁴ is aleaving group (e.g., halogen atoms such as chlorine, bromine, iodineetc.; substituted sulfonic acid esters such as methanesulfonic acidester, p-toluenesulfonic acid ester etc.; diazonio group), or hydroxy.

In reaction (k), compound (XVII) is reacted with compound (XVIII) togive compound (IIa).

This reaction is performed using about 1-10 mol of compound (XVIII) per1 mol of compound (XVII) in an organic solvent that does not adverselyinfluence the reaction.

Compound (XVII), which is the starting material compound of thisreaction, can be produced according to a method analogous to theproduction method shown in the aforementioned reaction (d), (f), (i) or(j).

When E³ is a leaving group (e.g., halogen atoms such as chlorine,bromine, iodine etc.; substituted sulfonic acid esters such astrifluoromethanesulfonic acid ester etc., and the like), and E⁴ ishydroxy, this reaction can be promoted according to a method known perse, for example, the method described in Journal of the AmericanChemical Society vol. 127, page 8146 (2005) and the like, or a methodanalogous thereto, in the presence of a metal catalyst. Examples of themetal catalyst include palladium compounds (e.g., palladium acetate,palladium chloride, tetrakis(triphenylphosphine)palladium,dichlorobis(triphenylphosphine)palladium,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium etc.), coppercompounds (e.g., copper powder, copper(I) chloride, copper(I) iodide,copper(I) acetate etc.), nickel compounds (e.g.,tetrakis(triphenylphosphine)nickel etc.), rhodium compounds (e.g.,tris(triphenylphosphine)rhodium chloride etc.), platinum compounds andthe like.

The amount of the metal catalyst to be used is about 0.000001 mol-5 mol,preferably 0.0001 mol-1 mol, per 1 mol of compound (XVII).

This reaction may be performed in the presence of a base and/or aligand. Examples of the base include metal alkoxides such as potassiumphenoxide, sodium tert-butoxide and the like; inorganic salts such aspotassium carbonate, sodium carbonate, cesium carbonate, potassiumphosphate etc., and the like. Examples of the ligand include organicphosphorus compounds such as triphenylphosphine,tri-tert-butylphosphine, tri-cyclohexylphosphine, BINAP(2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) and the like; organicamine compounds such as N,N′-dimethyl-cyclohexane-1,2-diamine,2,2-bipyridyl etc., and the like.

Examples of the solvent that does not adversely influence the reactioninclude ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane andthe like; halogenated hydrocarbons such as chloroform, dichloromethaneand the like; aromatic hydrocarbons such as benzene, toluene, xylene andthe like; amides such as N,N-dimethylformamide and the like; sulfoxidessuch as dimethyl sulfoxide etc., and the like. These solvents may beused in a mixture of two or more kinds thereof at an appropriate ratio.Furthermore, water may be mixed at an appropriate ratio.

When a metal catalyst unstable to oxygen is used, this reaction ispreferably performed under an inert gas (e.g., argon, nitrogen etc.)atmosphere.

The reaction temperature is generally about −50° C. to about 150° C.,preferably about −10° C. to about 120° C.

The reaction time is generally about 0.5-about 20 hr.

When E³ and E⁴ are hydroxy, this reaction is performed according to amethod known per se, for example, the method described in OrganicReactions vol. 42, page 335 (1992) and the like, or a method analogousthereto. In other words, this reaction is generally performed in thepresence of an organic phosphorus compound and an azo reagent in asolvent that does not adversely influence the reaction.

Examples of the organic phosphorus compound include triphenylphosphine,tri(n-butyl)phosphine and the like.

Examples of the azo reagent include diethyl azodicarboxylate,diisopropyl azodicarboxylate, azodicarbonyl dipiperazine and the like.

The amount of the organic phosphorus compound and azo reagent to be usedis preferably about 1-about 5 mol per 1 mol of compound (XVII).

Examples of the solvent that does not adversely influence the reactioninclude ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane andthe like; halogenated hydrocarbons such as chloroform, dichloromethaneand the like; aromatic hydrocarbons such as benzene, toluene, xylene andthe like; amides such as N,N-dimethylformamide and the like; sulfoxidessuch as dimethyl sulfoxide etc., and the like. These solvents may beused in a mixture of two or more kinds thereof at an appropriate ratio.

The reaction temperature is generally about −50° C. to about 150° C.,preferably about −10° C. to about 100° C.

The reaction time is generally about 0.5-about 20 hr.

When E³ is hydroxy, and E⁴ is a leaving group (e.g., halogen atoms suchas chlorine, bromine, iodine etc.; substituted sulfonic acid esters suchas trifluoromethanesulfonic acid ester etc., and the like), thisreaction is performed according to a conventional method in the presenceof a base in a solvent that does not adversely influence the reaction.

Examples of the base include alkali metal salts such as potassiumhydroxide, sodium hydroxide, sodium hydrogen carbonate, potassiumcarbonate and the like; amines such as pyridine, triethylamine,N,N-dimethylaniline, 1,8-diazabicyclo[5.4.0]undec-7-ene and the like;metal hydrides such as potassium hydride, sodium hydride and the like;alkali metal alkoxides such as sodium methoxide, sodium ethoxide,potassium tert-butoxide etc., and the like.

The amount of the base to be used is preferably about 1-about 5 mol per1 mol of compound (XVII).

Examples of the solvent that does not adversely influence the reactioninclude aqueous basic solutions such as 50% aqueous sodium hydroxidesolution, 50% aqueous potassium hydroxide solution and the like;aromatic hydrocarbons such as benzene, toluene, xylene and the like;nitriles such as acetonitrile, propionitrile and the like; ethers suchas tetrahydrofuran, 1,4-dioxane, diethyl ether and the like; ketonessuch as acetone, 2-butanone and the like; halogenated hydrocarbons suchas chloroform, dichloromethane and the like; amides such asN,N-dimethylformamide and the like; sulfoxides such as dimethylsulfoxide etc., and the like. These solvents may be used in a mixture oftwo or more kinds thereof at an appropriate ratio.

When a mixed solvent containing a basic aqueous solution is used in thisreaction, the reaction is preferably performed using a phase transfercatalyst such as tetrabutylammonium hydrogensulfate and the like.

The reaction temperature is generally about −50° C. to about 150° C.,preferably about −10° C. to about 100° C.

The reaction time is generally about 0.5-about 20 hr.

Particularly, when E³ is hydroxy and E⁴ is diazonio, this reaction isperformed according to a method known per se, for example, the methoddescribed in Tetrahedron Letters vol. 38, page 2733 (1982) and the like,or a method analogous thereto, in the presence of a metal catalyst in asolvent that does not adversely influence the reaction.

Examples of the metal catalyst include rhodium compounds (rhodium (II)acetate, rhodium(II) trifluoroacetate etc.), copper and salts thereof(e.g., copper(II) acetate, copper(II) chloride etc.), palladiumcomplexes (e.g., palladium acetate, palladium chloride,tetrakis(triphenylphosphine)palladium,dichlorobis(triphenylphosphine)palladium,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium etc.), nickelcompounds (e.g., tetrakis(triphenylphosphine)nickel etc.), platinumcompounds and the like. Of these, rhodium compounds are preferable.

The amount of the metal catalyst to be used is about 0.000001 mol-5 mol,preferably 0.0001 mol-1 mol, per 1 mol of compound (VIII).

Examples of the solvent that does not adversely influence the reactioninclude aromatic hydrocarbons such as benzene, toluene, xylene and thelike; ethers such as tetrahydrofuran, 1,4-dioxane, diethyl ether and thelike; ketones such as acetone, 2-butanone and the like; halogenatedhydrocarbons such as chloroform, dichloromethane and the like; amidessuch as N,N-dimethylformamide and the like; sulfoxides such as dimethylsulfoxide etc., and the like. These solvents may be used in a mixture oftwo or more kinds thereof at an appropriate ratio.

When a metal catalyst unstable to oxygen is used, this reaction ispreferably performed under an inert gas (e.g., argon, nitrogen etc.)atmosphere.

The reaction temperature is generally about −50° C. to about 150° C.,preferably about −10° C. to about 100° C. The reaction time is generallyabout 0.5-about 20 hr.

wherein X, Y, Z, W, A, R² and R³ are as defined above, R⁹ is optionallysubstituted C₁₋₆ alkylene (e.g., methylene, ethylene, propylene etc.),an optionally substituted 3- to 10-membered nonaromatic cyclic group oran optionally substituted 5- or 6-membered aromatic cyclic group, R¹⁰ isa hydrogen atom, optionally substituted C₁₋₆ alkyl, or optionallysubstituted C₃₋₁₀ cycloalkyl, each of which optionally has anindependent substituent or forms a ring between substituents.

In reaction (l), compound (XX) is reacted with compound (XXI) to givecompound (IIb). This reaction is generally performed using about 1-10mol of compound (XXI) per 1 mol of compound (XX) in an organic solventthat does not adversely influence the reaction. This reaction may beperformed in the presence of a base.

Compound (XX), which is the starting material compound of this reaction,can be produced according to a method analogous to the production methodshown in the aforementioned reaction (d), (f), (i) or (j).

Examples of the organic solvent that does not adversely influence thereaction include amides such as N,N-dimethylformamide,N,N-dimethylacetamide and the like; ethers such as 1,4-dioxane,tetrahydrofuran and the like; aromatic hydrocarbons such as benzene,toluene, trichlorobenzene and the like; and anilines such as aniline,N,N-diethylaniline and the like. These solvents may be used in a mixtureof two or more kinds thereof at an appropriate ratio.

The base is not particularly limited as long as the reaction proceedsand, for example, alkali metal salts such as potassium hydroxide, sodiumhydroxide, sodium hydrogen carbonate, potassium carbonate and the like;amines such as pyridine, triethylamine, N,N-dimethylaniline,1,8-diazabicyclo[5.4.0]undec-7-ene and the like; metal hydrides such aspotassium hydride, sodium hydride and the like; and alkali metalalkoxides such as potassium tert-butoxide and the like can be mentioned.

The reaction temperature is generally about −50° C. to about 300° C.,preferably about 25° C. to about 200° C.

The reaction time is generally about 1-about 48 hr.

wherein X, Y, Z, W, A, R², R³ and R⁷ are as defined above, R¹² isoptionally substituted C₁₋₆ alkylene (e.g., methylene, ethylene,propylene etc.), optionally substituted C₃₋₁₀ cycloalkylene (e.g.,cyclopropylene, cyclopentylene, cyclohexylene), optionally substitutedC₆₋₁₄ arylene or optionally substituted C₇₋₁₆ aralkylene, R¹³ is C₁₋₆alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,tert-butoxycarbonyl etc.), R¹⁴ is optionally substituted C₁₋₆ alkyl,optionally substituted C₃₋₁₀ cycloalkyl, and M is a metal (e.g.,magnesium, lithium, copper, zinc, tin etc.).

In reaction (m), compound (IIa-1) is reacted with alkylmetal (XXII) togive compound (IIc). This reaction is generally performed by using about2-10 mol of alkylmetal (XXII) per 1 mol of compound (IIa-1) in anorganic solvent that does not adversely influence the reaction.

Examples of the organic solvent that does not adversely influence thereaction include ethers such as 1,4-dioxane, tetrahydrofuran and thelike; and aromatic hydrocarbons such as benzene, toluene,trichlorobenzene and the like. These solvents may be used in a mixtureof two or more kinds thereof at an appropriate ratio.

The reaction temperature is generally about −50° C. to about 150° C.,preferably about −10° C. to about 100° C.

The reaction time is generally about 0.5-about 20 hr.

wherein X, Y, Z, W, A, R², R³ and R⁷ are as defined above, and R¹⁵ isoptionally substituted C₂₋₅ alkylene (e.g., ethylene, propylene etc.).

In reaction (n), the ketal moiety of compound (XXII) is subjected toring opening to give compound (IId).

This reaction is performed according to a method known per se, forexample, the method described in Journal of Organic Chemistry vol. 58,page 6756 (1993) and the like, or a method analogous thereto. In otherwords, this reaction is performed in the presence of a hydride reducingagent in a solvent that does not adversely influence the reaction.

Examples of the hydride reducing agent include aluminum hydride,diisobutylaluminum hydride, sodium cyanoborohydride, borane-dimethylsulfide complex, triethylsilane and the like.

The amount of the hydride reducing agent to be used is preferably about1-about 10 mol per 1 mol of compound (XXII).

Examples of the solvent that does not adversely influence the reactioninclude ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane andthe like; halogenated hydrocarbons such as chloroform, dichloromethaneand the like; aromatic hydrocarbons such as benzene, toluene, xylene andthe like, and the like. These solvents may be used in a mixture of twoor more kinds thereof at an appropriate ratio.

The above-mentioned reaction may be performed in the presence of a Lewisacid. Examples of the Lewis acid include aluminum chloride, borontrifluoride-diethylether complex, titanium tetrachloride and the like.

The reaction temperature is generally about −78° C. to about 150° C.,preferably about −78° C. to about 100° C.

The reaction time is generally about 0.5-about 20 hr.

In each reaction of the aforementioned (a)-(n), when the startingmaterial compound has hydroxy, amino (including —NH— and —NH₂—), carboxyor carbonyl, a protecting group such as those generally used in thepeptide chemistry may be introduced into these groups. By removing theprotecting group after the reaction as necessary, the object compoundcan be obtained.

Examples of the hydroxy-protecting group include C₁₋₆ alkyl (e.g.,methyl, ethyl, propyl, isopropyl, butyl, tert-butyl), phenyl, trityl,C₇₋₁₀ aralkyl (e.g., benzyl), formyl, C₁₋₆ alkyl-carbonyl (e.g., acetyl,propionyl), benzoyl, C₇₋₁₀ aralkyl-carbonyl (e.g., benzylcarbonyl),2-tetrahydropyranyl, 2-tetrahydrofuranyl, silyl (e.g., trimethylsilyl,triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl,tert-butyldiethylsilyl), C₂₋₆ alkenyl (e.g., 1-allyl) and the like.These groups may be substituted by 1 to 3 substituents selected from ahalogen atom (e.g., fluorine, chlorine, bromine, iodine), C₁₋₆ alkyl(e.g., methyl, ethyl, propyl), C₁₋₆ alkoxy (e.g., methoxy, ethoxy,propoxy), nitro and the like.

Examples of the amino-protecting group include formyl, C₁₋₆alkyl-carbonyl (e.g., acetyl, propionyl), C₁₋₆ alkoxy-carbonyl (e.g.,methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl), benzoyl, C₇₋₁₀aralkyl-carbonyl (e.g., benzylcarbonyl), C₇₋₁₄ aralkyloxy-carbonyl(e.g., benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl), trityl,phthaloyl, N,N-dimethylaminomethylene, silyl (e.g., trimethylsilyl,triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl,tert-butyldiethylsilyl), C₂₋₆ alkenyl (e.g., 1-allyl) and the like.These groups may be substituted by 1 to 3 substituents selected from ahalogen atom (e.g., fluorine, chlorine, bromine, iodine), C₁₋₆ alkoxy(e.g., methoxy, ethoxy, propoxy), nitro and the like.

Examples of the carboxy-protecting group include C₁₋₆ alkyl (e.g.,methyl, ethyl, propyl, isopropyl, butyl, tert-butyl), C₇₋₁₁ aralkyl(e.g., benzyl), phenyl, trityl, silyl (e.g., trimethylsilyl,triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl,tert-butyldiethylsilyl, tert-butyldiphenylsilyl), C₂₋₆ alkenyl (e.g.,1-allyl) and the like. These groups may be substituted by 1 to 3substituents selected from a halogen atom (e.g., fluorine, chlorine,bromine, iodine), C₁₋₆ alkoxy (e.g., methoxy, ethoxy, propoxy), nitroand the like.

Examples of the carbonyl-protecting group include cyclic acetal (e.g.,1,3-dioxane), non-cyclic acetal (e.g., di-C₁₋₆ alkylacetal) and thelike.

In addition, these protecting groups may be removed according to amethod known per se, for example, the method described in ProtectiveGroups in Organic Synthesis, John Wiley and Sons (1980) and the like.For example, a method using an acid, a base, ultraviolet rays,hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate,tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide(e.g., trimethylsilyl iodide, trimethylsilyl bromide etc.) and the like,a reduction method and the like can be used.

When compound (I) contains an optical isomer, a stereoisomer, aregioisomer or a rotamer, these are also encompassed in compound (I),and can be obtained as a single product according to synthesis andseparation methods known per se. For example, when compound (I) has anoptical isomer, an optical isomer resolved from this compound is alsoencompassed in compound (I).

The optical isomer can be produced by a method known per se. To bespecific, an optically active synthetic intermediate is used, or thefinal racemate product is subjected to optical resolution according to aconventional method to give an optical isomer.

The method of optical resolution may be a method known per se, such as afractional recrystallization method, a chiral column method, adiastereomer method, etc.

1) Fractional Recrystallization Method

A method wherein a salt of a racemate with an optically active compound(e.g., (+)-mandelic acid, (−)-mandelic acid, (+)-tartaric acid,(−)-tartaric acid, (+)-1-phenethylamine, (−)-1-phenethylamine,(+)-cinchonine, (−)-cinchonidine, brucine, etc.) is formed, which isseparated by a fractional recrystallization method, and if desired, afree optical isomer is obtained by a neutralization step.

2) Chiral Column Method

A method wherein a racemate or a salt thereof is applied to a column forseparation of an optical isomer (a chiral column) to allow separation.In the case of a liquid chromatography, for example, a mixture of theoptical isomers is applied to a chiral column such as ENANTIO-OVM(manufactured by Tosoh Corporation), CHIRAL series (manufactured byDaicel Chemical Industries, Ltd.) and the like, and developed withwater, various buffers (e.g., phosphate buffer, etc.) and organicsolvents (e.g., ethanol, methanol, isopropanol, acetonitrile,trifluoroacetic acid, diethylamine, etc.) solely or in admixture toseparate the optical isomer.

3) Diastereomer Method

A method wherein a racemic mixture is prepared into a diastereomericmixture by chemical reaction with an optically active reagent, which ismade into a single substance by a typical separation means (e.g., afractional recrystallization method, a chromatography method, etc.) andthe like, and is subjected to a chemical treatment such as hydrolysisand the like to separate an optically active reagent moiety, whereby anoptical isomer is obtained. For example, when compound (I) containshydroxy, or primary or secondary amino in a molecule, the compound andan optically active organic acid (e.g., MTPA[α-methoxy-α-(trifluoromethyl)phenylacetic acid], (−)-menthoxyaceticacid, etc.) and the like are subjected to condensation reaction to givediastereomers in the ester form or in the amide form, respectively. Whencompound (I) has a carboxyl group, this compound and an optically activeamine or an alcohol reagent are subjected to condensation reaction togive diastereomers in the amide form or in the ester form, respectively.The separated diastereomer is converted to an optical isomer of theoriginal compound by acid hydrolysis or base hydrolysis.

The present invention is explained in more detail in the following byreferring to Experimental Examples, Reference Examples, Examples andPreparation Examples, which are not to be construed as limitative.

In the following Reference Examples and Examples, % means weight %unless otherwise indicated. In addition, the room temperature means1-30° C.

In the following Reference Examples and Examples, the Dess-Martinreagent refers to commercially available1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one.

In the NMR spectrum, the chemical shift is expressed in δ value (ppm)and the coupling constant is expressed in Hz.

In the case of a mixed solvent, the numerical value indicated in theparenthesis is a volume mixing ratio of each solvent. In addition, % ofa solution means the number of grams in 100 mL of the solution. The unitof sample to concentration (c) in specific optical rotation ([α]_(D)) isg/dL. The abbreviations used in the present specification mean thefollowing.

s: singlet

d: doublet

t: triplet

q: quartet

dd: double doublet

dt: double triplet

m: multiplet

br: broad

J: coupling constant

CDCl₃: deuterated chloroform

DMSO-d₆: dimethyl sulfoxide-d₆

¹H NMR: proton nuclear magnetic resonance

MeOH: methanol

n-Hex: n-hexane

IPA: isopropanol

Reference Example 14′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

A solution of 5-methyl-4H-1,2,4-triazol-3-amine (1.7 g) and ethyl2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (7.1 g) in1,2,4-trichlorobenzene (70 mL) was stirred at 190° C. for 6 hr. Afterevaporation of the solvent under reduced pressure, ethyl acetate wasadded to the obtained residue. The precipitated solid was collected byfiltration to give the title compound as a colorless solid (3.6 g, 44%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.4, 3H), 1.47-1.65 (m, 2H), 2.31(s, 3H), 2.87-2.97 (m, 2H), 3.94 (s, 2H), 7.34-7.41 (m, 2H), 7.45-7.62(m, 4H), 7.77 (t, J=7.8, 1H), 7.93 (d, J=7.6, 1H), 12.95 (br s, 1H)

Reference Example 24′-[(2,4-dimethyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

A mixture of4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(1 g), methyl iodide (0.19 mL), potassium carbonate (0.41 g) andN,N-dimethylformamide (10 mL) was stirred at room temperature for 16 hr.The reaction mixture was diluted with ethyl acetate, washed with 5%aqueous potassium hydrogensulfate solution and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.67 g, 67%).

¹H NMR (300 MHz, CDCl₃) δ 1.04 (t, J=6.8, 3H), 1.63-1.80 (m, 2H), 2.46(s, 3H), 2.95-3.06 (m, 2H), 3.69 (s, 3H), 4.02 (s, 2H), 7.33-7.52 (m,6H), 7.56-7.66 (m, 1H), 7.74 (d, J=7.6, 1H)

Reference Example 34′-{[2-methyl-4-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

To a suspension (5 mL) of4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.15 g), (2-methyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid (0.13 g),triethylamine (0.15 mL), pyridine (0.3 mL) and molecular sieves 4A (0.3g) in dichloromethane was added copper(II) acetate (0.14 g), and themixture was stirred for 16 hr. The reaction mixture was diluted withethyl acetate, insoluble material was filtered off through celite, andthe filtrate was concentrated. The residue was purified by silica gelcolumn chromatography to give the title compound as a colorless solid(0.17 g, 87%).

¹H NMR (300 MHz, CDCl₃) δ 1.10 (t, J=7.2, 3H), 1.49 (d, J=6.4, 3H),1.67-1.86 (m, 2H), 2.39 (s, 3H), 2.87 (dd, J=15.7, 7.8, 1H), 2.99-3.19(m, 2H), 3.36 (dd, J=15.7, 8.9, 1H), 4.03 (s, 2H), 4.86-5.10 (m, 1H),6.86 (d, J=8.3, 1H), 7.02-7.21 (m, 2H), 7.33-7.55 (m, 6H), 7.56-7.68 (m,1H), 7.74 (d, J=7.6, 1H)

Reference Example 44′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

A solution of 4H-1,2,4-triazol-3-amine (2.4 g) and ethyl2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (10 g) in1,2,4-trichlorobenzene (50 mL) was stirred at 180° C. for 6 hr. Afterevaporation of the solvent under reduced pressure, the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (4 g, 38%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.2, 3H), 1.51-1.68 (m, 2H),2.90-3.03 (m, 2H), 3.97 (s, 2H), 7.37-7.44 (m, 2H), 7.45-7.63 (m, 4H),7.72-7.83 (m, 1H), 7.93 (d, J=7.6, 1H), 8.12 (s, 1H), 13.13 (s, 1H)

Reference Example 54′-{[4-(4-fluorobenzyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.5 g), 1-(bromomethyl)-4-fluorobenzene (0.2 mL), potassium carbonate(0.38 g) and N,N-dimethylformamide (10 mL) was stirred at roomtemperature for 16 hr. The reaction mixture was diluted with ethylacetate, washed with 5% aqueous potassium hydrogensulfate solution andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.58 g, 89%).

¹H NMR (300 MHz, CDCl₃) δ 1.05 (t, J=7.4, 3H), 1.62-1.83 (m, 2H),2.96-3.08 (m, 2H), 4.03 (s, 2H), 5.38 (s, 2H), 6.94-7.06 (m, 2H),7.32-7.52 (m, 6H), 7.53-7.67 (m, 3H), 7.75 (d, J=7.6, 1H), 7.94 (s, 1H)

Reference Example 64′-{[2-methyl-4-(4-fluorobenzyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.7 g), 1-(bromomethyl)-4-fluorobenzene (0.27 mL), potassium carbonate(0.51 g) and N,N-dimethylformamide (15 mL) was stirred at roomtemperature for 16 hr. The reaction mixture was diluted with ethylacetate, washed with 5% aqueous potassium hydrogensulfate solution andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.56 g, 62%).

¹H NMR (300 MHz, CDCl₃) δ 1.03 (t, J=7.4, 3H), 1.63-1.77 (m, 2H), 2.46(s, 3H), 2.92-3.02 (m, 2H), 4.00 (s, 2H), 5.34 (s, 2H), 7.00 (t, J=8.7,2H), 7.30-7.50 (m, 6H), 7.55-7.66 (m, 3H), 7.74 (d, J=7.6, 1H)

Reference Example 74′-[(2-cyclopropyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

A solution of 5-cyclopropyl-4H-1,2,4-triazol-3-amine (1 g) and ethyl2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (2.8 g) in1,2,4-trichlorobenzene (20 mL) was stirred at 180° C. for 6 hr. Afterevaporation of the solvent under reduced pressure, the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.7 g, 21%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.81-1.02 (m, 7H) 1.50-1.72 (m, 2H)1.98-2.07 (m, 1H) 2.81-3.01 (m, 2H) 3.93 (s, 2H) 7.35-7.42 (m, 2H)7.44-7.53 (m, 2H) 7.52-7.64 (m, 2H) 7.72-7.82 (m, 1H) 7.93 (dd, J=7.7,0.9 Hz, 1H) 12.93 (s, 1H)

Reference Example 84′-{[2-cyclopropyl-4-(4-fluorobenzyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(2-cyclopropyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.5 g), 1-(bromomethyl)-4-fluorobenzene (0.17 mL), potassium carbonate(0.34 g) and N,N-dimethylformamide (10 mL) was stirred at roomtemperature for 16 hr. The reaction mixture was diluted with ethylacetate, washed with 5% aqueous potassium hydrogensulfate solution andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.44 g, 70%).

¹H NMR (300 MHz, CDCl₃) δ 0.90-1.14 (m, 7H), 1.61-1.77 (m, 2H),1.99-2.14 (m, 1H), 2.90-3.03 (m, 2H), 3.99 (s, 2H), 5.30 (s, 2H),6.93-7.06 (m, 2H), 7.28-7.37 (m, 2H), 7.37-7.55 (m, 4H), 7.54-7.67 (m,3H), 7.74 (d, J=8.0, 1H)

Reference Example 94′-({4-[(6-ethylpyridin-3-yl)methyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(1.5 g), (6-ethylpyridin-3-yl)methanol (0.46 g) and tributylphosphine(1.1 mL) in THF (50 mL) was added 1,1′-(azodicarbonyl)dipiperidine (0.88g) at 0° C., and the mixture was stirred at room temperature overnight.The reaction mixture was diluted with ethyl acetate, washed with 5%aqueous potassium hydrogensulfate solution and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.43 g, 49%).

¹H NMR (300 MHz, CDCl₃) δ 0.93 (t, J=7.2, 3H), 1.23-1.31 (m, 3H),1.50-1.62 (m, 2H), 2.45 (s, 3H), 2.79 (q, J=7.6, 2H), 2.92-3.01 (m, 2H),4.00 (s, 2H), 5.36 (s, 2H), 7.12 (d, J=8.0, 1H), 7.31-7.51 (m, 6H),7.57-7.67 (m, 1H), 7.74 (d, J=7.6, 1H), 7.85 (dd, J=8.0, 2.3, 1H), 8.79(d, J=1.9, 1H)

Reference Example 104′-[(4-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

A mixture of4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.5 g), methyl iodide (0.1 mL), potassium carbonate (0.38 g) andN,N-dimethylformamide (10 mL) was stirred at room temperature for 16 hr.The reaction mixture was diluted with ethyl acetate, washed with 5%aqueous potassium hydrogensulfate solution and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.52 g, 100%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.4, 3H), 1.65-1.83 (m, 2H),3.01-3.13 (m, 2H), 3.72 (s, 3H), 4.04 (s, 2H), 7.35-7.53 (m, 6H),7.56-7.68 (m, 1H), 7.74 (d, J=7.6, 1H), 7.94 (s, 1H)

Reference Example 114′-{[4-(2,2-dimethylpropyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.5 g), 1-iodo-2,2-dimethylpropane (0.36 mL), cesium carbonate (0.89 g)and N,N-dimethylacetamide (10 mL) was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with 5% aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.4 g,67%).

¹H NMR (300 MHz, CDCl₃) δ 0.98-1.13 (m, 12H), 1.66-1.84 (m, 2H),2.96-3.10 (m, 2H), 4.04 (s, 2H), 4.18 (s, 2H), 7.34-7.54 (m, 6H),7.59-7.70 (m, 1H), 7.74 (d, J=7.6, 1H), 7.90 (s, 1H)

Reference Example 124′-{[4-(3,3-dimethyl-2-oxobutyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(1 g), 1-bromo-3,3-dimethylbutan-2-one (0.4 mL), potassium carbonate(0.75 g) and N,N-dimethylformamide (15 mL) was stirred at roomtemperature for 3 hr. The reaction mixture was diluted with ethylacetate, washed with 5% aqueous potassium hydrogensulfate solution andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.4 g, 32%).

¹H NMR (300 MHz, CDCl₃) δ 1.00-1.10 (m, 3H), 1.31 (s, 9H), 1.65-1.80 (m,2H), 2.98-3.09 (m, 2H), 4.04 (s, 2H), 5.21 (s, 2H), 7.30-7.55 (m, 6H),7.58-7.66 (m, 1H), 7.74 (d, J=6.8, 1H), 7.87 (s, 1H)

Reference Example 134′-({4-[2-(4-fluorophenyl)-2-oxoethyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(1 g), 2-bromo-1-(4-fluorophenyl)ethanone (0.65 mL), potassium carbonate(0.75 g) and N,N-dimethylformamide (15 mL) was stirred at roomtemperature for 3 hr. The reaction mixture was diluted with ethylacetate, washed with 5% aqueous potassium hydrogensulfate solution andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.78 g, 57%).

¹H NMR (300 MHz, CDCl₃) δ 1.08 (t, J=7.4, 3H), 1.68-1.85 (m, 2H),3.01-3.14 (m, 2H), 4.06 (s, 2H), 5.66 (s, 2H), 7.19 (t, J=8.5, 2H),7.33-7.53 (m, 6H), 7.57-7.66 (m, 1H), 7.75 (d, J=6.8, 1H), 7.88 (s, 1H),8.01-8.13 (m, 2H)

Reference Example 144′-({4-[2-(4-fluorophenyl)-2-hydroxyethyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution (15 mL) of4′-({4-[2-(4-fluorophenyl)-2-oxoethyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.78 g) in methanol was added sodium borohydride (0.12 g), and themixture was stirred at room temperature for 1 hr. After evaporation ofthe solvent under reduced pressure, the residue was extracted with waterand ethyl acetate. The obtained ethyl acetate layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.78 g, 100%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.2, 3H), 1.65-1.80 (m, 2H),3.01-3.08 (m, 2H), 4.03 (s, 2H), 4.07-4.11 (m, 1H), 4.47-4.65 (m, 2H),5.18-5.28 (m, 1H), 7.04 (t, J=8.5, 2H), 7.32 (d, J=8.3, 2H), 7.39-7.52(m, 6H), 7.60-7.67 (m, 1H), 7.75 (d, J=8.0, 1H), 7.94 (s, 1H)

Reference Example 154′-({4-[2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-fluorophenyl)ethyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a mixture of4′-({4-[2-(4-fluorophenyl)-2-hydroxyethyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.78 g), 2,6-lutidine (0.27 mL) and tetrahydrofuran (20 mL) was addedtert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.53 mL), and themixture was stirred at room temperature for 5 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.56 g,58%).

¹H NMR (300 MHz, CDCl₃) δ −0.37-−0.33 (m, 3H), −0.32-−0.27 (m, 3H),0.60-0.72 (m, 9H), 1.07 (t, J=7.3, 3H), 1.65-1.80 (m, 2H), 2.99-3.16 (m,2H), 3.98-4.09 (m, 2H), 4.19 (dd, J=13.1, 3.7, 1H), 4.53 (dd, J=13.0,9.6, 1H), 5.30 (dd, J=9.6, 3.8, 1H), 6.94-7.10 (m, 2H), 7.33-7.53 (m,8H), 7.58-7.66 (m, 1H), 7.75 (dd, J=7.7, 0.9, 1H), 7.94 (s, 1H)

Reference Example 16 tert-butyl{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}acetate

A mixture of4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(9 g), tert-butyl bromoacetate (3.8 mL), potassium carbonate (6 g) andN,N-dimethylformamide (100 mL) was stirred at room temperature for 3 hr.The reaction mixture was diluted with ethyl acetate, washed with 5%aqueous potassium hydrogensulfate solution and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (2.6 g, 25%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.3, 3H), 1.44-1.52 (m, 9H),1.65-1.82 (m, 2H), 2.96-3.11 (m, 2H), 4.05 (s, 2H), 4.88 (s, 2H),7.32-7.52 (m, 6H), 7.57-7.67 (m, 1H), 7.74 (dd, J=7.7, 0.9, 1H), 7.91(s, 1H)

Reference Example 174′-{[4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.8 g), (2-bromoethoxy)(tert-butyl)dimethylsilane (0.7 mL), potassiumcarbonate (0.6 g), sodium iodide (0.033 g) and N,N-dimethylformamide (15mL) was stirred at 50° C. for 16 hr. The reaction mixture was dilutedwith ethyl acetate, washed with 5% aqueous potassium hydrogensulfatesolution and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.82 g, 71%).

¹H NMR (300 MHz, CHLOROFORM-d) δ −0.08 (s, 6H) 0.76 (s, 9H) 1.05 (t,J=7.4 Hz, 3H) 1.62-1.79 (m, 2H) 2.99-3.12 (m, 2H) 3.96-4.06 (m, 4H) 4.43(t, J=5.9 Hz, 2H) 7.33-7.53 (m, 6H) 7.57-7.68 (m, 1H) 7.74 (dd, J=7.7,0.8 Hz, 1H) 7.92 (s, 1H)

Reference Example 18{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}aceticacid

A mixture of tert-butyl{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}acetate(1.78 g) and trifluoroacetic acid (15 mL) was stirred at roomtemperature for 1 hr. The reaction mixture was diluted with toluene (15mL) and the solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (1.44 g, 92%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.96 (t, J=7.4, 3H), 1.54-1.71 (m, 2H),2.98-3.07 (m, 2H), 4.03 (s, 2H), 4.80 (s, 2H), 7.38-7.44 (m, 2H),7.47-7.62 (m, 4H), 7.73-7.82 (m, 1H), 7.93 (d, J=7.6, 1H), 8.21 (s, 1H),13.33 (br. s., 1H)

Reference Example 192-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}acetamide

A mixture of{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}aceticacid (0.5 g), 1-hydroxybenzotriazole ammonium salt (0.24 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.27 g) andN,N-dimethylformamide (10 mL) was stirred at room temperature for 15 hr.The reaction mixture was diluted with ethyl acetate, washed with 1 Nhydrochloric acid and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.48 g,100%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.96 (t, J=7.3, 3H), 1.54-1.70 (m, 2H),2.95-3.06 (m, 2H), 4.02 (s, 2H), 4.67 (s, 2H), 7.28 (s, 1H), 7.38-7.43(m, 2H), 7.46-7.61 (m, 4H), 7.68-7.81 (m, 2H), 7.93 (dd, J=7.7, 0.8,1H), 8.17 (s, 1H)

Reference Example 204′-{[4-(1-methylethyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.8 g), 2-iodopropane (0.43 mL), potassium carbonate (0.6 g) andN,N-dimethylacetamide (10 mL) was stirred at 100° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with 5% aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.48 g,53%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.4, 3H), 1.30 (s, 3H), 1.33 (s,3H), 1.70-1.87 (m, 2H), 3.11-3.25 (m, 2H), 4.08 (s, 2H), 5.47-5.60 (m,1H), 7.24-7.32 (m, 2H), 7.37-7.53 (m, 4H), 7.57-7.68 (m, 1H), 7.75 (d,J=7.6, 1H), 8.18-8.27 (m, 1H)

Reference Example 214′-{[4-(2-hydroxy-2-methylpropyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.8 g), isobutylene oxide (1.9 mL), potassium carbonate (0.6 g) andN,N-dimethylacetamide (5 mL) was stirred in a sealed tube at 100° C. for16 hr. The reaction mixture was diluted with ethyl acetate, washed with5% aqueous potassium hydrogensulfate solution and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.76 g, 79%).

¹H NMR (300 MHz, CDCl₃) δ 1.07 (t, J=7.4, 3H), 1.30 (s, 6H), 1.67-1.80(m, 2H), 3.00-3.11 (m, 2H), 4.05 (s, 2H), 4.22 (s, 1H), 4.41 (s, 2H),7.32-7.52 (m, 6H), 7.63 (t, J=7.6, 1H), 7.75 (d, J=6.4, 1H), 7.92 (s,1H)

Reference Example 224′-({4-[(1-methyl-1H-benzimidazol-2-yl)methyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a mixture of{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}aceticacid (0.9 g), oxalyl chloride (0.22 mL) and tetrahydrofuran (50 mL) wasadded N,N-dimethylformamide (several drops), and the mixture was stirredat room temperature for 2 hr. The reaction mixture was concentratedunder reduced pressure, the obtained residue was dissolved inN,N-dimethylacetamide (5 mL) and added to a solution ofN-methylbenzene-1,2-diamine (1.2 mL) in N,N-dimethylacetamide (5 mL).The reaction mixture was stirred at room temperature for 2 hr, dilutedwith ethyl acetate, washed with water and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. Then, a mixture of the obtained residue in acetic acid(20 mL) was stirred at 100° C. for 4 hr. The reaction mixture wasconcentrated and the obtained residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.84 g,78%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.3, 3H), 1.65-1.80 (m, 2H),2.99-3.10 (m, 2H), 3.96 (s, 3H), 4.04 (s, 2H), 5.68 (s, 2H), 7.16-7.49(m, 9H), 7.58-7.77 (m, 3H), 7.95 (s, 1H)

Reference Example 234′-[(4-ethyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

A mixture of4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.5 g), ethyl iodide (0.38 mL), potassium carbonate (0.13 g) andN,N-dimethylformamide (10 mL) was stirred at room temperature for 16 hr.The reaction mixture was diluted with ethyl acetate, washed with 5%aqueous potassium hydrogensulfate solution and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.55 g, 100%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.4 Hz, 3H), 1.41 (t, J=7.1Hz, 3H), 1.65-1.79 (m, 2H), 2.98-3.09 (m, 2H), 4.04 (s, 2H), 4.33 (q,J=7.0 Hz, 2H), 7.34-7.53 (m, 6H), 7.57-7.66 (m, 1H), 7.75 (dd, J=7.7,0.9 Hz, 1H), 7.94 (s, 1H)

Reference Example 244′-{[4-(cyclopropylmethyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.5 g), (bromomethyl)cyclopropane (0.16 mL), potassium carbonate (0.38g) and N,N-dimethylacetamide (10 mL) was stirred at 70° C. for 16 hr.The reaction mixture was diluted with ethyl acetate, washed with 5%aqueous potassium hydrogensulfate solution and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.54 g, 93%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.49-0.60 (m, 4H), 1.07 (t, J=7.3 Hz,3H), 1.37-1.50 (m, 1H), 1.65-1.80 (m, 2H), 2.98-3.13 (m, 2H), 4.05 (s,2H), 4.13-4.19 (m, 2H), 7.35-7.53 (m, 6H), 7.57-7.67 (m, 1H), 7.75 (dd,J=7.7, 0.9 Hz, 1H), 7.92 (s, 1H)

Reference Example 254′-{[2-methyl-4-(1-methylethyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.8 g), 2-iodopropane (0.4 mL), potassium carbonate (0.55 g) andN,N-dimethylacetamide (10 mL) was stirred at 100° C. for 5 hr. Thereaction mixture was diluted with ethyl acetate, washed with 5% aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.24 g,28%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.04 (t, J=7.3 Hz, 3H) 1.56-1.78 (m,8H) 2.44 (s, 3H) 2.90-3.01 (m, 2H) 4.00 (s, 2H) 5.30-5.46 (m, 1H)7.32-7.52 (m, 6H) 7.57-7.67 (m, 1H) 7.74 (dd, J=7.7, 1.3 Hz, 1H)

Reference Example 264′-{[4-(2-hydroxybutyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.5 g), 2-ethyloxirane (1.17 mL), potassium carbonate (0.38 g) andN,N-dimethylacetamide (10 mL) was stirred in a sealed tube at 100° C.for 8 hr. The reaction mixture was diluted with ethyl acetate, washedwith 5% aqueous potassium hydrogensulfate solution and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.45 g, 75%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.00-1.12 (m, 6H), 1.52-1.81 (m, 4H),2.99-3.10 (m, 2H), 3.18 (d, J=6.2 Hz, 1H), 3.92-4.06 (m, 3H), 4.28-4.47(m, 2H), 7.33-7.52 (m, 6H), 7.57-7.69 (m, 1H), 7.75 (dd, J=7.7, 0.9 Hz,1H), 7.92 (s, 1H)

Reference Example 274′-[(2-cyclopropyl-4-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

A mixture of4′-[(2-cyclopropyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.18 g), methyl iodide (0.033 mL), potassium carbonate (0.12 g) andN,N-dimethylformamide (10 mL) was stirred at room temperature for 16 hr.The reaction mixture was diluted with ethyl acetate, washed with 5%aqueous potassium hydrogensulfate solution and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.2 g, 100%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.98-1.08 (m, 7H), 1.64-1.79 (m, 2H),2.00-2.11 (m, 1H), 2.95-3.04 (m, 2H), 3.65 (s, 3H), 4.01 (s, 2H),7.32-7.52 (m, 6H), 7.57-7.66 (m, 1H), 7.71-7.77 (m, 1H)

Reference Example 284′-({4-[4-(1-methylethoxy)phenyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a suspension (15 mL) of4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.5 g), [4-(1-methylethoxy)phenyl]boronic acid (0.49 g), triethylamine(0.5 mL), pyridine (1 mL) and molecular sieves 4A (1 g) indichloromethane was added copper(II) acetate (0.49 g), and the mixturewas stirred for 16 hr. The reaction mixture was diluted with ethylacetate, insoluble material was filtered off through celite, and thefiltrate was concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.17 g,82%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.11 (t, J=7.3 Hz, 3H), 1.35 (s, 3H),1.37 (s, 3H), 1.71-1.89 (m, 2H), 3.06-3.16 (m, 2H), 4.07 (s, 2H),4.51-4.63 (m, 1H), 6.98-7.06 (m, 2H), 7.28-7.35 (m, 2H), 7.38-7.53 (m,6H), 7.58-7.67 (m, 1H), 7.71-7.76 (m, 1H), 7.86 (s, 1H)

Reference Example 29 methyl4-({6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}methyl)benzoate

A mixture of4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(5 g), methyl 4-(bromomethyl)benzoate (3.7 mL), potassium carbonate (2.3g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for5 hr. The reaction mixture was diluted with ethyl acetate, washed with5% aqueous potassium hydrogensulfate solution and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (2.8 g, 40%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.05 (t, J=7.3 Hz, 3H), 1.64-1.81 (m,2H), 2.97-3.09 (m, 2H), 3.86-3.93 (m, 3H), 4.04 (s, 2H), 5.46 (s, 2H),7.33-7.53 (m, 6H), 7.57-7.70 (m, 3H), 7.75 (dd, J=7.7, 0.9 Hz, 1H), 7.94(s, 1H), 7.96-8.03 (m, 2H)

Reference Example 304′-({4-[4-hydroxymethylbenzyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of methyl4-({6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}methyl)benzoate(2.8 g), 1N aqueous sodium hydroxide solution (30 mL), tetrahydrofuran(30 mL) and methanol (30 mL) was stirred at 50° C. for 3 hr. 1 NHydrochloric acid was added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The obtained ethyl acetate layer waswashed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The obtained residuewas dissolved in tetrahydrofuran (50 mL), N-methylmorpholine (0.67 mL)and ethyl chlorocarbonate (0.58 mL) was added at 0° C., and the mixturewas stirred at the same temperature for 2 hr. The reaction mixture wascooled to −15° C., sodium borohydride (0.57 g) and methanol (10 mL) wereadded, and the mixture was allowed to gradually warm to roomtemperature. The reaction mixture was extracted with saturated aqueousammonium chloride solution and ethyl acetate. The ethyl acetate layerwas washed with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (1.86 g, 70%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.05 (t, J=7.4 Hz, 3H), 1.63-1.79 (m,2H), 2.96-3.08 (m, 2H), 4.03 (s, 2H), 4.65 (s, 2H), 5.42 (s, 2H),7.28-7.52 (m, 8H), 7.55-7.67 (m, 3H), 7.74 (d, J=8.0 Hz, 1H), 7.94 (s,1H)

Reference Example 314′-{[4-(4-formylbenzyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-({4-[4-hydroxymethylbenzyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(1.3 g), manganese dioxide (7.0 g) and methylene chloride (15 mL) wasstirred at room temperature for 16 hr. The insoluble material wasfiltered off through celite, and the filtrate was concentrated to givethe title compound as a colorless solid (1.3 g, 96%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.3 Hz, 3H), 1.65-1.83 (m,2H), 3.00-3.10 (m, 2H), 4.04 (s, 2H), 5.48 (s, 2H), 7.33-7.53 (m, 6H),7.58-7.67 (m, 1H), 7.67-7.78 (m, 3H), 7.81-7.88 (m, 2H), 7.94 (s, 1H),9.98 (s, 1H)

Reference Example 324′-({4-[4-(1-hydroxyethyl)benzyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

4′-{[4-(4-Formylbenzyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(1.3 g) was dissolved in tetrahydrofuran (30 mL), and methylmagnesiumbromide (1.0 M tetrahydrofuran solution, 2.8 mL) was added at −78° C.The reaction mixture was warmed to 0° C., and stirred for 6 hr.Saturated aqueous ammonium chloride solution was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The obtainedethyl acetate layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (1.2 g,90%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.05 (t, J=7.3 Hz, 3H), 1.46 (d, J=6.4Hz, 3H), 1.63-1.76 (m, 2H), 1.83 (d, J=3.6 Hz, 1H), 2.98-3.06 (m, 2H),4.03 (s, 2H), 4.81-4.92 (m, 1H), 5.41 (s, 2H), 7.31-7.51 (m, 8H),7.54-7.66 (m, 3H), 7.75 (dd, J=7.7, 0.9 Hz, 1H), 7.94 (s, 1H)

Reference Example 334′-({4-[4-(1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)benzyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a mixture of4′-({4-[4-(1-hydroxyethyl)benzyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(1.2 g), 2,6-lutidine (0.41 mL) and tetrahydrofuran (30 mL) was addedtert-butyldimethylsilyl trifluoromethanesulfonate (0.79 mL) at 0° C.,and the mixture was stirred at the same temperature for 3 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography to give the title compound as acolorless solid (1.4 g, 100%).

¹H NMR (300 MHz, CHLOROFORM-d) δ −0.05 (s, 3H), 0.03 (s, 3H), 0.88 (s,9H), 1.05 (t, J=7.4 Hz, 3H), 1.36 (d, J=6.1 Hz, 3H), 1.63-1.77 (m, 2H),2.96-3.07 (m, 2H), 4.04 (s, 2H), 4.84 (q, J=6.4 Hz, 1H), 5.40 (s, 2H),7.24-7.31 (m, 2H), 7.33-7.55 (m, 8H), 7.58-7.67 (m, 1H), 7.74 (d, J=8.0Hz, 1H), 7.94 (s, 1H)

Reference Example 344′-[(5-oxo-4,7-dipropyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

A mixture of4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.5 g), 1-iodopropane (0.16 mL), potassium carbonate (0.38 g) andN,N-dimethylformamide (10 mL) was stirred at room temperature for 16 hr.The reaction mixture was diluted with ethyl acetate, washed with 5%aqueous potassium hydrogensulfate solution and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.5 g, 90%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.96-1.12 (m, 6H) 1.65-1.78 (m, 2H)1.78-1.94 (m, 2H) 2.99-3.09 (m, 2H) 4.04 (s, 2H) 4.17-4.27 (m, 2H)7.35-7.52 (m, 6H) 7.57-7.67 (m, 1H) 7.75 (dd, J=7.8, 0.8 Hz, 1H) 7.93(s, 1H)

Reference Example 354′-[(5-oxo-4-phenyl-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

To a suspension (20 mL) of4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.6 g), phenylboronic acid (0.4 g), triethylamine (0.5 mL), pyridine (1mL) and molecular sieves 4A (1 g) in dichloromethane was addedcopper(II) acetate (0.59 g), and the mixture was stirred for 16 hr. Thereaction mixture was diluted with ethyl acetate, insoluble material wasfiltered off through celite, and the filtrate was concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.58 g, 80%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.12 (t, J=7.3 Hz, 3H), 1.72-1.90 (m,2H), 3.07-3.19 (m, 2H), 4.07 (s, 2H), 7.35-7.67 (m, 12H), 7.75 (dd,J=7.7, 0.9 Hz, 1H), 7.87 (s, 1H)

Reference Example 364′-({2-methyl-4-[4-(1-methylethoxy)phenyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a suspension (40 mL) of4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(1 g), [4-(1-methylethoxy)phenyl]boronic acid (0.9 g), triethylamine (1mL), pyridine (2 mL) and molecular sieves 4A (2 g) in dichloromethanewas added copper(II) acetate (0.91 g), and the mixture was stirred for48 hr. The reaction mixture was diluted with ethyl acetate, insolublematerial was filtered off through celite, and the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.55 g,43%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.10 (t, J=7.3 Hz, 3H), 1.34 (s, 3H),1.36 (s, 3H), 1.72-1.85 (m, 2H), 2.39 (s, 3H), 2.98-3.16 (m, 2H), 4.03(s, 2H), 4.48-4.65 (m, 1H), 6.94-7.07 (m, 2H), 7.22-7.35 (m, 2H),7.36-7.52 (m, 6H), 7.61 (dd, J=7.6, 1.4 Hz, 1H), 7.74 (dd, J=7.7, 0.9Hz, 1H)

Reference Example 374′-{[4-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

To a suspension (20 mL) of4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.6 g), (2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid (0.62g), triethylamine (0.5 mL), pyridine (1 mL) and molecular sieves 4A (1g) in dichloromethane was added copper(II) acetate (0.59 g), and themixture was stirred for 48 hr. The reaction mixture was diluted withethyl acetate, insoluble material was filtered off through celite, andthe filtrate was concentrated. The residue was purified by silica gelcolumn chromatography to give the title compound as a colorless solid(0.86 g, 100%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.11 (t, J=7.3 Hz, 3H), 1.50 (s, 6H),1.72-1.89 (m, 2H), 3.08 (s, 2H), 3.09-3.18 (m, 2H), 4.06 (s, 2H), 6.85(d, J=8.5 Hz, 1H), 7.09-7.18 (m, 2H), 7.37-7.52 (m, 6H), 7.57-7.66 (m,1H), 7.75 (dd, J=7.7, 0.9 Hz, 1H), 7.87 (s, 1H)

Reference Example 383′-fluoro-4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

A solution of 5-methyl-4H-1,2,4-triazol-3-amine (8.9 g) and ethyl2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (25 g) in1,2,4-trichlorobenzene (120 mL) was stirred at 180° C. for 16 hr. Afterevaporation of the solvent under reduced pressure, ethyl acetate wasadded to the obtained residue. The precipitated solid was collected byfiltration to give the title compound as a colorless solid (11.8 g,43%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.3 Hz, 3H) 1.53-1.70 (m, 2H)2.90-3.01 (m, 2H) 3.94 (s, 2H) 7.27-7.50 (m, 3H) 7.55-7.68 (m, 2H)7.74-7.85 (m, 1H) 7.92-7.99 (m, 1H) 8.12 (s, 1H) 13.13 (s, 1H)

Reference Example 394′-{[4-(2,4-dimethoxybenzyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile

A mixture of3′-fluoro-4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(1 g), 1,1′-(azodicarbonyl)dipiperidine (1.3 g), tributylphosphine (1.6mL), (2,4-dimethoxyphenyl)methanol (0.58 g) and tetrahydrofuran (50 mL)was stirred at room temperature for 4 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 1 N hydrochloric acid and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.36 g, 26%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.4 Hz, 3H), 1.64-1.80 (m,2H), 3.02-3.10 (m, 2H), 3.76 (s, 6H), 4.06 (s, 2H), 5.41 (s, 2H),6.35-6.49 (m, 3H), 7.00 (d, J=8.3 Hz, 1H), 7.21-7.29 (m, 1H), 7.36-7.49(m, 3H), 7.64 (t, J=7.8 Hz, 1H), 7.75 (d, J=7.6 Hz, 1H), 7.91 (s, 1H)

Reference Example 404′-{[4-(4-methoxyphenyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

To a suspension (20 mL) of4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.5 g), (4-methoxyphenyl)boronic acid (0.41 g), triethylamine (0.5 mL),pyridine (1 mL) and molecular sieves 4A (1 g) in dichloromethane wasadded copper(II) acetate (0.49 g), and the mixture was stirred for 16hr. The reaction mixture was diluted with ethyl acetate, insolublematerial was filtered off through celite, and the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.64 g,99%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.11 (t, J=7.3 Hz, 3H), 1.73-1.88 (m,2H), 3.06-3.20 (m, 2H), 3.81-3.87 (m, 3H), 4.07 (s, 2H), 7.02-7.09 (m,2H), 7.32-7.51 (m, 8H), 7.58-7.66 (m, 1H), 7.75 (dd, J=7.7, 0.9 Hz, 1H),7.86 (s, 1H)

Reference Example 413′-fluoro-4′-[(5-oxo-4-phenyl-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

To a suspension (20 mL) of3′-fluoro-4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.5 g), phenylboronic acid (0.31 g), triethylamine (0.5 mL), pyridine(1 mL) and molecular sieves 4A (1 g) in dichloromethane was addedcopper(II) acetate (0.47 g), and the mixture was stirred for 16 hr. Thereaction mixture was diluted with ethyl acetate, insoluble material wasfiltered off through celite, and the filtrate was concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.61 g, 100%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.12 (t, J=7.4 Hz, 3H), 1.73-1.88 (m,2H), 3.11-3.21 (m, 2H), 4.09 (s, 2H), 7.21-7.31 (m, 2H), 7.39-7.68 (m,9H), 7.72-7.78 (m, 1H), 7.87 (s, 1H)

Reference Example 424′-{[4-(methoxymethyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile

A mixture of3′-fluoro-4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.5 g), chloro(methoxy)methane (0.12 mL), potassium carbonate (0.36 g)and N,N-dimethylformamide (10 mL) was stirred at room temperature for 1hr. The reaction mixture was diluted with ethyl acetate, washed with 5%aqueous potassium hydrogensulfate solution and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.38 g, 69%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.07 (t, J=7.3 Hz, 3H), 1.64-1.80 (m,2H), 3.03-3.12 (m, 2H), 3.52 (s, 3H), 4.05 (s, 2H), 5.67 (s, 2H),7.22-7.29 (m, 2H), 7.36-7.50 (m, 3H), 7.59-7.69 (m, 1H), 7.72-7.79 (m,1H), 7.94 (s, 1H)

Reference Example 433′-fluoro-4′-({4-[4-(1-methylethoxy)phenyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a suspension (20 mL) of3′-fluoro-4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.5 g), [4-(1-methylethoxy)phenyl]boronic acid (0.46 g), triethylamine(0.5 mL), pyridine (1 mL) and molecular sieves 4A (1 g) indichloromethane was added copper(II) acetate (0.47 g), and the mixturewas stirred for 16 hr. The reaction mixture was diluted with ethylacetate, insoluble material was filtered off through celite, and thefiltrate was concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.59 g,100%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.11 (t, J=7.3 Hz, 3H) 1.36 (d, J=6.2Hz, 6H) 1.71-1.86 (m, 2H) 3.10-3.20 (m, 2H) 4.07 (s, 2H) 4.50-4.65 (m,1H) 6.97-7.07 (m, 2H) 7.21-7.36 (m, 4H) 7.40-7.55 (m, 3H) 7.60-7.68 (m,1H) 7.76 (dd, J=8.0, 1.0 Hz, 1H) 7.87 (s, 1H)

Reference Example 44 methyl2-[(2′-cyano-2-fluorobiphenyl-4-yl)methyl]-3-oxoheptanoate

A solution of methyl 3-oxoheptanoate (7 g) in tetrahydrofuran (30 mL)was added to a mixture of sodium hydride (1.2 g) and tetrahydrofuran (80mL) at room temperature, and the mixture was stirred at room temperaturefor 30 min. And then, 4′-(bromomethyl)-2′-fluorobiphenyl-2-carbonitrile(5.3 g) was added to the reaction mixture, and the reaction mixture wasstirred at room temperature for 3 days. The reaction mixture wasconcentrated, the residue was extracted with 5% aqueous potassiumhydrogensulfate solution and then with ethyl acetate, and the ethylacetate layer was washed with saturated brine and concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless oil (7.3 g, 90%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.75-0.86 (m, 3H), 1.10-1.47 (m, 4H),2.41-2.66 (m, 2H), 3.03-3.22 (m, 2H), 3.62 (s, 3H), 4.22 (t, J=7.6 Hz,1H), 7.14-8.01 (m, 7H)

Reference Example 454′-({4-[4-(1-methylethoxy)phenyl]-5-oxo-7-butyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a suspension (15 mL) of4′-[(7-butyl-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.5 g), [4-(1-methylethoxy)phenyl]boronic acid (0.47 g), triethylamine(0.5 mL), pyridine (1 mL) and molecular sieves 4A (1 g) indichloromethane was added copper(II) acetate (0.47 g), and the mixturewas stirred for 16 hr. The reaction mixture was diluted with ethylacetate, insoluble material was filtered off through celite, and thefiltrate was concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.69 g,100%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.99 (t, J=7.3 Hz, 3H), 1.35 (d, J=6.2Hz, 6H), 1.45-1.57 (m, 2H), 1.65-1.82 (m, 2H), 3.07-3.19 (m, 2H), 4.06(s, 2H), 4.49-4.65 (m, 1H), 6.98-7.05 (m, 2H), 7.29-7.36 (m, 2H),7.38-7.53 (m, 6H), 7.58-7.67 (m, 1H), 7.75 (dd, J=7.7, 0.9 Hz, 1H), 7.87(s, 1H)

Reference Example 46 methyl2-[(2′-cyano-3,5-difluorobiphenyl-4-yl)methyl]-3-oxoheptanoate

A solution of methyl 3-oxoheptanoate (6 g) in tetrahydrofuran (50 mL)was added to a mixture of sodium hydride (1 g) and tetrahydrofuran (50mL) at room temperature, and the mixture was stirred at room temperaturefor 30 min. And then,4′-(bromomethyl)-3′,5′-difluorobiphenyl-2-carbonitrile (5.9 g) was addedto the reaction mixture, and the reaction mixture was stirred at roomtemperature for 3 days. The reaction mixture was concentrated, theresidue was extracted with 5% aqueous potassium hydrogensulfate solutionand then with ethyl acetate, and the ethyl acetate layer was washed withsaturated brine and concentrated. The residue was purified by silica gelcolumn chromatography to give the title compound as a colorless oil (7.2g, 98%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.88 (t, J=7.4 Hz, 3H), 1.20-1.36 (m,2H), 1.49-1.62 (m, 2H), 2.38-2.53 (m, 1H), 2.54-2.67 (m, 1H), 3.27 (d,J=6.8 Hz, 2H), 3.69-3.74 (m, 3H), 3.91 (t, J=7.6 Hz, 1H), 7.02-7.12 (m,2H), 7.43-7.53 (m, 2H), 7.66 (t, J=7.6 Hz, 1H), 7.77 (d, J=7.6 Hz, 1H)

Reference Example 474′-[(7-butyl-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]-3′,5′-difluorobiphenyl-2-carbonitrile

A solution of 4H-1,2,4-triazol-3-amine (2.4 g) and methyl2-[(2′-cyano-3,5-difluorobiphenyl-4-yl)methyl]-3-oxoheptanoate (10 g) in1,2,4-trichlorobenzene (50 mL) was stirred at 180° C. for 6 hr. Afterevaporation of the solvent under reduced pressure, ethyl acetate wasadded to the obtained residue. The precipitated solid was collected byfiltration to give the title compound as a colorless solid (4.5 g, 57%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.79-0.89 (m, 3H), 1.29-1.51 (m, 4H),2.94-3.04 (m, 2H), 3.98 (s, 2H), 7.29-7.40 (m, 2H), 7.57-7.70 (m, 2H),7.75-7.84 (m, 1H), 7.97 (dd, J=7.7, 0.9 Hz, 1H), 8.11 (s, 1H), 13.09 (s,1H)

Reference Example 484′-{[7-butyl-4-(methoxymethyl)-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′,5′-difluorobiphenyl-2-carbonitrile

A mixture of4′-[(7-butyl-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]-3′,5′-difluorobiphenyl-2-carbonitrile(0.88 g), chloro(methoxy)methane (0.19 mL), potassium carbonate (0.58 g)and N,N-dimethylformamide (15 mL) was stirred at room temperature for 1hr. The reaction mixture was diluted with ethyl acetate, washed with 5%aqueous potassium hydrogensulfate solution and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.77 g, 79%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.94 (t, J=7.2 Hz, 3H), 1.37-1.52 (m,2H), 1.53-1.70 (m, 2H), 2.04 (s, 3H), 3.03-3.13 (m, 2H), 4.06 (s, 2H),5.65 (s, 2H), 7.01-7.14 (m, 2H), 7.41-7.52 (m, 2H), 7.60-7.71 (m, 1H),7.77 (d, J=8.0 Hz, 1H), 7.93 (s, 1H)

Reference Example 494′-({7-butyl-4-[3-fluoro-4-methoxyphenyl]-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a suspension (15 mL) of4′-[(7-butyl-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.5 g), (3-fluoro-4-methoxyphenyl)boronic acid (0.44 g), triethylamine(0.5 mL), pyridine (1 mL) and molecular sieves 4A (1 g) indichloromethane was added copper(II) acetate (0.47 g), and the mixturewas stirred for 16 hr. The reaction mixture was diluted with ethylacetate, insoluble material was filtered off through celite, and thefiltrate was concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.78 g,100%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.99 (t, J=7.2 Hz, 3H), 1.45-1.56 (m,2H), 1.66-1.79 (m, 2H), 3.08-3.18 (m, 2H), 3.94 (s, 3H), 4.06 (s, 2H),7.02-7.24 (m, 3H), 7.37-7.52 (m, 6H), 7.63 (t, J=7.8 Hz, 1H), 7.74 (d,J=7.6 Hz, 1H), 7.87 (s, 1H)

Reference Example 504′-({7-butyl-4-[3-fluoro-4-(1-methylethoxy)phenyl]-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a suspension (15 mL) of4′-[(7-butyl-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.5 g), [3-fluoro-4-(1-methylethoxy)phenyl]boronic acid (0.51 g),triethylamine (0.5 mL), pyridine (1 mL) and molecular sieves 4A (1 g) indichloromethane was added copper(II) acetate (0.47 g), and the mixturewas stirred for 16 hr. The reaction mixture was diluted with ethylacetate, insoluble material was filtered off through celite, and thefiltrate was concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.68 g,98%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.99 (t, J=7.2 Hz, 3H), 1.40 (d, J=6.1Hz, 6H), 1.45-1.59 (m, 2H), 1.65-1.80 (m, 2H), 3.08-3.18 (m, 2H), 4.05(s, 2H), 4.52-4.67 (m, 1H), 7.04-7.23 (m, 3H), 7.38-7.52 (m, 6H),7.57-7.66 (m, 1H), 7.74 (d, J=7.6 Hz, 1H), 7.87 (s, 1H)

Reference Example 514′-({4-[4-(1-methylethyl)phenyl]]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a suspension (15 mL) of4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.5 g), [4-(1-methylethyl)phenyl]boronic acid (0.49 g), triethylamine(0.5 mL), pyridine (1 mL) and molecular sieves 4A (1 g) indichloromethane was added copper(II) acetate (0.49 g), and the mixturewas stirred for 16 hr. The reaction mixture was diluted with ethylacetate, insoluble material was filtered off through celite, and thefiltrate was concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.63 g,95%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.12 (t, J=7.3 Hz, 3H), 1.28 (d, J=6.8Hz, 6H), 1.73-1.86 (m, 2H), 2.92-3.04 (m, 1H), 3.09-3.18 (m, 2H), 4.07(s, 2H), 7.31-7.50 (m, 10H), 7.59-7.67 (m, 1H), 7.75 (dd, J=7.7, 0.9 Hz,1H), 7.87 (s, 1H)

Reference Example 524′-({4-[4-(1-hydroxy-1-methylethyl)phenyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a suspension (26 mL) of4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.86 g), (4-acetylphenyl)boronic acid (0.83 g), triethylamine (0.86mL), pyridine (1.7 mL) and molecular sieves 4A (1.7 g) indichloromethane was added copper(II) acetate (0.84 g), and the mixturewas stirred for 16 hr. The reaction mixture was diluted with ethylacetate, insoluble material was filtered off through celite, and thefiltrate was concentrated. Methyllithium (2.2M diethyl ether solution,0.94 mL) was added to the obtained residue at −78° C. The reactionmixture was stirred at the same temperature for 1 hr, and extracted withsaturated aqueous ammonium chloride solution and diethyl ether. Thediethyl ether layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.47 g,41%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.12 (t, J=7.4 Hz, 3H) 1.61 (s, 6H)1.74-1.83 (m, 2H) 3.10-3.18 (m, 2H) 4.07 (s, 2H) 7.38-7.77 (m, 12H) 7.87(s, 1H)

Reference Example 534′-{[4-(3-methoxyphenyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

To a suspension (15 mL) of4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.5 g), (3-methoxyphenyl)boronic acid (0.41 g), triethylamine (0.5 mL),pyridine (1 mL) and molecular sieves 4A (1 g) in dichloromethane wasadded copper(II) acetate (0.49 g), and the mixture was stirred for 16hr. The reaction mixture was diluted with ethyl acetate, insolublematerial was filtered off through celite, and the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.65 g,100%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.11 (t, J=7.4 Hz, 3H), 1.70-1.89 (m,2H), 3.07-3.19 (m, 2H), 3.82 (s, 3H), 4.07 (s, 2H), 6.95 (s, 1H),6.97-7.07 (m, 2H), 7.35-7.52 (m, 7H), 7.62 (t, J=7.8 Hz, 1H), 7.74 (d,J=7.6 Hz, 1H), 7.86 (s, 1H)

Reference Example 544′-{[4-(3,4-dimethoxyphenyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

To a suspension (15 mL) of4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.5 g), (3,4-dimethoxyphenyl)boronic acid (0.49 g), triethylamine (0.5mL), pyridine (1 mL) and molecular sieves 4A (1 g) in dichloromethanewas added copper(II) acetate (0.49 g), and the mixture was stirred for16 hr. The reaction mixture was diluted with ethyl acetate, insolublematerial was filtered off through celite, and the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.58 g,85%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.11 (t, J=7.2 Hz, 3H), 1.67-1.90 (m,2H), 3.06-3.18 (m, 2H), 3.88 (s, 3H), 3.92 (s, 3H), 4.07 (s, 2H), 6.90(d, J=1.9 Hz, 1H), 6.96-7.05 (m, 2H), 7.36-7.51 (m, 6H), 7.63 (t, J=7.0Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.86 (s, 1H)

Reference Example 554′-({4-[4-(1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a suspension (19 mL) of4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.65 g), (4-acetylphenyl)boronic acid (0.63 g), triethylamine (0.65mL), pyridine (1.3 mL) and molecular sieves 4A (1.3 g) indichloromethane was added copper(II) acetate (0.64 g), and the mixturewas stirred for 16 hr. The reaction mixture was diluted with ethylacetate, insoluble material was filtered off through celite, and thefiltrate was concentrated. The obtained residue was dissolved inmethanol (15 mL), sodium borohydride (0.059 g) was added, and themixture was stirred at room temperature for 1 hr. After evaporation ofthe solvent under reduced pressure, the residue was extracted with waterand ethyl acetate. The obtained ethyl acetate layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The obtained residue wasdissolved in tetrahydrofuran (15 mL), 2,6-lutidine (0.14 mL) andtert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.26 mL) were addedand the mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.49 g,45%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.03 (s, 3H), 0.09 (s, 3H), 0.93 (s,9H), 1.13 (t, J=7.4 Hz, 3H), 1.44 (d, J=6.2 Hz, 3H), 1.76-1.87 (m, 2H),3.10-3.18 (m, 2H), 4.08 (s, 2H), 4.95 (q, J=6.4 Hz, 1H), 7.35-7.55 (m,10H), 7.59-7.67 (m, 1H), 7.76 (dd, J=7.7, 0.9 Hz, 1H), 7.89 (s, 1H)

Reference Example 564′-{[4-(4-fluorophenyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

To a suspension (15 mL) of4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.5 g), (4-fluorophenyl)boronic acid (0.38 g), triethylamine (0.5 mL),pyridine (1 mL) and molecular sieves 4A (1 g) in dichloromethane wasadded copper(II) acetate (0.49 g), and the mixture was stirred for 16hr. The reaction mixture was diluted with ethyl acetate, insolublematerial was filtered off through celite, and the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.57 g,91%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.12 (t, J=7.3 Hz, 3H), 1.73-1.88 (m,2H), 3.04-3.18 (m, 2H), 4.03 (s, 2H), 7.16-7.29 (m, 2H), 7.36-7.53 (m,8H), 7.57-7.67 (m, 1H), 7.75 (dd, J=7.7, 0.9 Hz, 1H), 7.87 (s, 1H)

Reference Example 574′-{[4-(3-fluoro-4-methoxyphenyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

To a suspension (15 mL) of4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.5 g), (3-fluoro-4-methoxyphenyl)boronic acid (0.45 g), triethylamine(0.5 mL), pyridine (1 mL) and molecular sieves 4A (1 g) indichloromethane was added copper(II) acetate (0.49 g), and the mixturewas stirred for 16 hr. The reaction mixture was diluted with ethylacetate, insoluble material was filtered off through celite, and thefiltrate was concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.6 g,90%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.11 (t, J=7.4 Hz, 3H) 1.71-1.84 (m,2H) 3.04-3.19 (m, 2H) 3.94 (s, 3H) 4.07 (s, 2H) 7.03-7.28 (m, 3H)7.37-7.53 (m, 6H) 7.56-7.67 (m, 1H) 7.75 (dd, J=7.7, 0.8 Hz, 1H) 7.87(s, 1H)

Reference Example 584′-{[5-oxo-7-propyl-4-(thiophen-3-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

To a suspension (15 mL) of4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.5 g), thiophen-3-ylboronic acid (0.35 g), triethylamine (0.5 mL),pyridine (1 mL) and molecular sieves 4A (1 g) in dichloromethane wasadded copper(II) acetate (0.49 g), and the mixture was stirred for 16hr. The reaction mixture was diluted with ethyl acetate, insolublematerial was filtered off through celite, and the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.52 g,85%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.11 (t, J=7.3 Hz, 3H) 1.70-1.87 (m,2H) 3.06-3.16 (m, 2H) 4.07 (s, 2H) 7.22-7.32 (m, 1H) 7.37-7.52 (m, 7H)7.57-7.67 (m, 2H) 7.75 (dd, J=7.7, 0.9 Hz, 1H) 7.90 (s, 1H)

Reference Example 594′-{[2-methyl-4-(1-methylpropyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(1.5 g), 2-iodobutane (1.4 mL), potassium carbonate (1 g) andN,N-dimethylacetamide (15 mL) was stirred at 100° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with 5% aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.36 g,22%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.86 (t, J=7.4 Hz, 3H), 1.04 (t, J=7.3Hz, 3H), 1.59 (t, J=3.4 Hz, 3H), 1.63-1.79 (m, 2H), 1.88-2.02 (m, 1H),2.15-2.32 (m, 1H), 2.44 (s, 3H), 2.90-3.02 (m, 2H), 4.00 (s, 2H),5.02-5.19 (m, 1H), 7.30-7.37 (m, 2H), 7.39-7.51 (m, 4H), 7.58-7.66 (m,1H), 7.74 (dd, J=7.7, 0.9 Hz, 1H)

Reference Example 604′-({2-methyl-4-[(1-methylcyclopropyl)methyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(1.5 g), (1-methylcyclopropyl)methanol (0.44 g) and tributylphosphine(1.9 mL) in THF (100 mL) was added 1,1′-(azodicarbonyl)dipiperidine (1.9g) under ice-cooling, and the mixture was stirred at room temperatureovernight. The reaction mixture was diluted with ethyl acetate, washedwith 5% aqueous potassium hydrogensulfate solution and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.36 g, 21%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.30-0.36 (m, 2H), 0.76-0.84 (m, 2H),0.99-1.10 (m, 6H), 1.64-1.80 (m, 2H), 2.41-2.46 (m, 3H), 2.93-3.04 (m,2H), 4.03 (s, 2H), 4.20 (s, 2H), 7.32-7.51 (m, 6H), 7.56-7.65 (m, 1H),7.74 (dd, J=7.8, 0.8 Hz, 1H)

Reference Example 614′-{[4-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(5 g), (3-bromo-2,2-dimethylpropoxy)(tert-butyl)dimethylsilane (4.7 mL),cesium carbonate (8.1 g) and N,N-dimethylacetamide (50 mL) was stirredat 100° C. for 16 hr. The reaction mixture was diluted with ethylacetate, washed with 5% aqueous potassium hydrogensulfate solution andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (2 g, 28%).

¹H NMR (300 MHz, CHLOROFORM-d) δ −0.02 (s, 6H), 0.86 (s, 9H), 0.98 (s,6H), 1.05 (t, J=7.4 Hz, 3H), 1.65-1.78 (m, 2H), 2.42 (s, 3H), 2.91-3.02(m, 2H), 3.47 (s, 2H), 4.02 (s, 2H), 4.21 (s, 2H), 7.32-7.51 (m, 6H),7.57-7.65 (m, 1H), 7.75 (d, J=7.6 Hz, 1H)

Reference Example 624′-({2-methyl-5-oxo-4-[(1-phenylcyclopropyl)methyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(1.5 g), (1-phenylcyclopropyl)methanol (0.87 g) and tributylphosphine (2mL) in THF (100 mL) was added 1,1′-(azodicarbonyl)dipiperidine (2 g) at0° C., and the mixture was stirred at room temperature overnight. Thereaction mixture was diluted with ethyl acetate, washed with 5% aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.43 g,21%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.94 (d, J=1.5 Hz, 4H), 1.02 (t, J=7.3Hz, 3H), 1.66-1.77 (m, 2H), 2.53 (s, 3H), 3.06-3.15 (m, 2H), 4.02 (s,2H), 4.54 (s, 2H), 7.11-7.32 (m, 7H), 7.37-7.49 (m, 4H), 7.59-7.68 (m,1H), 7.72-7.80 (m, 1H)

Reference Example 634′-{[4-(3-hydroxy-2,2-dimethylpropyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-{[4-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(1.5 g), tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 4mL) and tetrahydrofuran (30 mL) was stirred at room temperature for 3hr. The reaction mixture was extracted with ethyl acetate and water, andthe organic layer was washed with water and then with saturated brine,and dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography to give the title compound as a colorless solid(0.98 g, 79%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.98 (s, 6H) 1.06 (t, J=7.4 Hz, 3H)1.65-1.79 (m, 2H) 2.42 (s, 3H) 2.95-3.03 (m, 2H) 3.10 (d, J=7.6 Hz, 2H)4.02 (s, 2H) 4.05-4.26 (m, 2H) 5.31 (t, J=7.8 Hz, 1H) 7.31-7.51 (m, 6H)7.58-7.66 (m, 1H) 7.74 (d, J=7.6 Hz, 1H)

Reference Example 644′-{[4-(cyclohex-2-en-1-yl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(5 g), sodium hydride (0.62 g) and N,N-dimethylformamide (50 mL) wasstirred at room temperature for 10 min, 3-bromocyclohexene (1.8 mL) wasadded, and the mixture was stirred at the same temperature for 16 hr.The reaction mixture was diluted with ethyl acetate, washed with 5%aqueous potassium hydrogensulfate solution and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (1 g, 17%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.04 (t, J=7.3 Hz, 3H) 1.53-2.57 (m,11H) 2.91-3.01 (m, 2H) 3.93-4.07 (m, 2H) 5.57-5.95 (m, 3H) 7.32-7.51 (m,6H) 7.58-7.66 (m, 1H) 7.74 (dd, J=7.7, 0.9 Hz, 1H)

Reference Example 654′-{[4-(3,3-dimethyl-2-oxobutyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(3 g), 1-bromo-3,3-dimethylbutan-2-one (1.1 mL), potassium carbonate(2.1 g) and N,N-dimethylformamide (30 mL) was stirred at roomtemperature for 16 hr. The reaction mixture was diluted with ethylacetate, washed with 5% aqueous potassium hydrogensulfate solution andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.53 g, 15%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.04 (t, J=7.4 Hz, 3H), 1.31 (s, 9H),1.65-1.80 (m, 2H), 2.39 (s, 3H), 2.92-3.02 (m, 2H), 4.01 (s, 2H), 5.17(s, 2H), 7.31-7.36 (m, 2H), 7.38-7.50 (m, 4H), 7.59-7.65 (m, 1H), 7.74(dd, J=7.7, 0.9 Hz, 1H)

Reference Example 664′-{[4-(2-hydroxy-3,3-dimethylbutyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

To a solution (10 mL) of4′-{[4-(3,3-dimethyl-2-oxobutyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(1.4 g) in methanol was added sodium borohydride (0.017 g), and themixture was stirred at room temperature for 2 hr. After evaporation ofthe solvent under reduced pressure, the residue was extracted with waterand ethyl acetate. The obtained ethyl acetate layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (1.2 g, 84%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.01-1.09 (m, 12H), 1.65-1.77 (m, 2H),2.42 (s, 3H), 2.93-3.04 (m, 2H), 3.58-3.68 (m, 2H), 3.94-4.18 (m, 3H),4.65 (d, J=14.7 Hz, 1H), 7.30-7.51 (m, 6H), 7.58-7.67 (m, 1H), 7.74 (dd,J=7.7, 0.9 Hz, 1H)

Reference Example 674′-{[4-(2-methoxy-3,3-dimethylbutyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-{[4-(2-hydroxy-3,3-dimethylbutyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.3 g), sodium hydride (0.03 g) and N,N-dimethylformamide (5 mL) wasstirred at 0° C. for 10 min, methyl iodide (0.046 mL) was added, and themixture was stirred at room temperature for 16 hr. The reaction mixturewas diluted with ethyl acetate, washed with 5% aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.22 g,72%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.98-1.10 (m, 12H), 1.66-1.79 (m, 2H),2.42-2.48 (m, 3H), 2.95-3.08 (m, 2H), 3.12 (s, 3H), 3.52 (dd, J=9.9, 3.1Hz, 1H), 4.04 (s, 2H), 4.21 (dd, J=13.1, 3.1 Hz, 1H), 4.48 (dd, J=13.0,10.0 Hz, 1H), 7.33-7.49 (m, 6H), 7.58-7.65 (m, 1H), 7.74 (dd, J=7.7, 0.9Hz, 1H)

Reference Example 684′-{[4-(2-{[tert-butyl(dimethyl)silyl]oxy}-3,3-dimethylbutyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

To a mixture of4′-{[4-(2-hydroxy-3,3-dimethylbutyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.9 g), 2,6-lutidine (0.32 mL) and tetrahydrofuran (20 mL) was addedtert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.64 mL), and themixture was stirred at room temperature for 5 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.9 g,81%).

¹H NMR (300 MHz, CHLOROFORM-d) δ −0.78 (s, 3H), −0.06 (s, 3H), 0.78 (s,9H), 0.98-1.08 (m, 12H), 1.62-1.78 (m, 2H), 2.43 (s, 3H), 2.90-3.10 (m,2H), 3.95-4.08 (m, 3H), 4.20-4.28 (m, 1H), 4.33-4.46 (m, 1H), 7.33-7.52(m, 6H), 7.57-7.68 (m, 1H), 7.75 (dd, J=7.8, 0.8 Hz, 1H)

Reference Example 694′-({2-methyl-4-[(3-methyloxetan-3-yl)methyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(1.5 g), (3-methyloxetan-3-yl)methanol (0.6 g) and tributylphosphine(1.9 mL) in THF (80 mL) was added 1,1′-(azodicarbonyl)dipiperidine (1.9g) under ice-cooling, and the mixture was stirred at room temperaturefor 16 hr. The reaction mixture was diluted with ethyl acetate, washedwith 5% aqueous potassium hydrogensulfate solution and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.03 g, 16%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.4 Hz, 3H), 1.40 (s, 3H),1.66-1.79 (m, 2H), 2.42 (s, 3H), 2.95-3.04 (m, 2H), 4.01 (s, 2H), 4.29(d, J=6.1 Hz, 2H), 4.35 (s, 2H), 4.81 (d, J=6.4 Hz, 2H), 7.31-7.51 (m,6H), 7.62 (t, J=7.6 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H)

Reference Example 705-methyl-N-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-amine

To a solution (40 mL) of 5-methyl-4H-1,2,4-triazol-3-amine (3 g) andtetrahydro-4H-pyran-4-one (3.7 g) in acetic acid was added sodiumcyanoborohydride (9.7 g), and the mixture was stirred at roomtemperature for 16 hr. Water was added to the reaction mixture, and thesolvent was evaporated under reduced pressure. The obtained residue waspoured into saturated aqueous sodium hydrogen carbonate, and the mixturewas extracted with a mixed solvent of ethyl acetate and isopropylalcohol (3:1). The obtained extract was dried over anhydrous sodiumsulfate, and the solvent was evaporated under reduced pressure to givethe title compound as a colorless solid (0.79 g, 14%).

¹H NMR (300 MHz, DMSO-d₆) δ 1.31-1.48 (m, 2H), 1.76-1.88 (m, 2H),1.96-2.21 (m, 2H), 3.26-3.37 (m, 3H), 3.37-3.53 (m, 1H), 3.79-3.88 (m,2H), 5.38-6.41 (m, 1H), 11.54-12.39 (m, 1H)

Reference Example 714′-{[2-methyl-5-oxo-7-propyl-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate(0.87 g) and5-methyl-N-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-amine (0.3 g)was stirred at 250° C. for 15 min under microwave irradiation. Theobtained reaction mixture was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.37 g,48%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.05 (t, J=7.3 Hz, 3H), 1.62-1.80 (m,4H), 2.45 (s, 3H), 2.92-3.10 (m, 4H), 3.54 (t, J=12.1 Hz, 2H), 4.00 (s,2H), 4.07-4.17 (m, 2H), 5.18-5.31 (m, 1H), 7.32-7.52 (m, 6H), 7.58-7.67(m, 1H), 7.75 (dd, J=7.7, 0.9 Hz, 1H)

Reference Example 72N-(2-methoxy-1-methylethyl)-5-methyl-4H-1,2,4-triazol-3-amine

To a solution (40 mL) of 5-methyl-4H-1,2,4-triazol-3-amine (2.5 g) and1-methoxypropan-2-one (2.7 g) in acetic acid was added sodiumcyanoborohydride (8.1 g), and the mixture was stirred at roomtemperature for 16 hr. Water was added to the reaction mixture, and thesolvent was evaporated under reduced pressure. The obtained residue waspoured into saturated aqueous sodium hydrogen carbonate, and the mixturewas extracted with a mixed solvent of ethyl acetate and isopropylalcohol (3:1). The obtained extract was dried over anhydrous sodiumsulfate, and the solvent was evaporated under reduced pressure to givethe title compound as a colorless solid (1.4 g, 32%).

¹H NMR (300 MHz, DMSO-d₆) δ 1.08 (d, J=6.4 Hz, 3H), 1.97-2.22 (m, 2H),3.11-3.39 (m, 6H), 3.65 (br. s., 1H), 5.14-6.14 (m, 1H), 11.49-12.35 (m,1H)

Reference Example 734′-{[4-(2-methoxy-1-methylethyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate(1.84 g) andN-(2-methoxy-1-methylethyl)-5-methyl-4H-1,2,4-triazol-3-amine (0.4 g)was stirred at 250° C. for 15 min under microwave irradiation. Theobtained reaction mixture was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.63 g,52%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.04 (t, J=7.3 Hz, 3H), 1.55 (d, J=7.2Hz, 3H), 1.65-1.79 (m, 2H), 2.43 (s, 3H), 2.91-3.01 (m, 2H), 3.31 (s,3H), 3.60 (dd, J=10.1, 5.4 Hz, 1H), 4.00 (s, 2H), 4.33 (t, J=9.9 Hz,1H), 5.44 (br. s., 1H), 7.31-7.51 (m, 6H), 7.56-7.66 (m, 1H), 7.74 (dd,J=7.7, 0.9 Hz, 1H)

Reference Example 74 N-cyclobutyl-5-methyl-4H-1,2,4-triazol-3-amine

To a solution (30 mL) of 5-methyl-4H-1,2,4-triazol-3-amine (2.5 g) andcyclobutanone (2.1 g) in acetic acid was added sodium cyanoborohydride(8.1 g), and the mixture was stirred at room temperature for 16 hr.Water was added to the reaction mixture, and the solvent was evaporatedunder reduced pressure. The obtained residue was poured into saturatedaqueous sodium hydrogen carbonate, and the mixture was extracted with amixed solvent of ethyl acetate and isopropyl alcohol (3:1). The obtainedextract was dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure to give the title compound as acolorless solid (2.4 g, 61%).

¹H NMR (300 MHz, DMSO-d₆) δ 1.46-1.68 (m, 2H), 1.75-2.31 (m, 7H),3.83-4.00 (m, 1H), 5.67-6.69 (m, 1H), 11.57-12.40 (m, 1H)

Reference Example 754′-[(4-cyclobutyl-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (1.8g) and N-cyclobutyl-5-methyl-4H-1,2,4-triazol-3-amine (0.4 g) wasstirred at 250° C. for 15 min under microwave irradiation. The obtainedreaction mixture was purified by silica gel column chromatography togive the title compound as a colorless solid (0.63 g, 52%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.04 (t, J=7.3 Hz, 3H), 1.63-2.05 (m,4H), 2.22-2.34 (m, 2H), 2.45 (s, 3H), 2.92-3.02 (m, 2H), 3.14-3.31 (m,2H), 3.99 (s, 2H), 5.42-5.59 (m, 1H), 7.32-7.52 (m, 6H), 7.58-7.66 (m,1H), 7.68-7.77 (m, 1H)

Reference Example 764′-{[2-methyl-5-oxo-4-(2-oxopropyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(3 g), sodium hydride (0.47 g) and N,N-dimethylformamide (15 mL) wasstirred at room temperature for 10 min, 1-chloropropan-2-one (0.75 mL)was added, and the mixture was stirred at room temperature for 16 hr.The reaction mixture was diluted with ethyl acetate, washed with 5%aqueous potassium hydrogensulfate solution and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.49 g, 14%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.05 (t, J=7.4 Hz, 3H), 1.63-1.80 (m,2H), 2.31 (s, 3H), 2.40 (s, 3H), 2.94-3.04 (m, 2H), 4.01 (s, 2H), 5.02(s, 2H), 7.31-7.50 (m, 6H), 7.57-7.66 (m, 1H), 7.74 (d, J=7.6 Hz, 1H)

Reference Example 774′-{[4-(2-{[tert-butyl(dimethyl)silyl]oxy}propyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-{[2-methyl-5-oxo-4-(2-oxopropyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.49 g), sodium borohydride (0.063 g) and methanol (20 mL) was stirredat room temperature for 2 hr. The reaction mixture was concentrated, andthe residue was extracted with ethyl acetate and saturated aqueousammonium chloride solution. The obtained ethyl acetate layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure. The obtained residue wasdissolved in tetrahydrofuran (15 mL), and 2,6-lutidine (0.19 mL) andtert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.38 mL) were addedat 0° C. The reaction mixture was stirred at 0° C. for 3 hr, dilutedwith ethyl acetate, washed with water and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.52 g,85%).

¹H NMR (300 MHz, CHLOROFORM-d) δ −0.78 (s, 3H) −0.06 (s, 3H) 0.78 (s,9H) 0.99-1.11 (m, 3H) 1.61 (s, 3H) 1.63-1.81 (m, 2H) 2.43 (s, 3H)2.90-3.09 (m, 2H) 3.94-4.08 (m, 3H) 4.20-4.30 (m, 1H) 4.32-4.46 (m, 1H)7.35-7.51 (m, 6H) 7.59-7.67 (m, 1H) 7.75 (dd, J=7.7, 0.9 Hz, 1H)

Reference Example 784′-{[4-(2-cyclohexyl-2-hydroxyethyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

To a mixture of cyclohexanecarbaldehyde (2.9 g), diiodomethane (2.5 mL)and tetrahydrofuran (80 mL) was added methyllithium (2.1M diethyl ethersolution, 25 mL) at 0° C., and the mixture was stirred at roomtemperature for 4 hr. The reaction mixture was extracted with diethylether and saturated aqueous ammonium chloride solution. The diethylether layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The obtained residue was dissolved in N,N-dimethylformamide (30 mL),4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(4 g) and potassium carbonate (2.9 g) were added, and the mixture wasstirred at 80° C. for 16 hr. The reaction mixture was diluted with ethylacetate, washed with 5% potassium hydrogensulfate and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The precipitated solid wascollected by filtration to give the title compound as a colorless solid(0.64 g, 12%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.05 (t, J=7.4 Hz, 3H), 1.16-1.31 (m,4H), 1.62-1.93 (m, 6H), 2.42 (s, 3H), 2.95-3.03 (m, 2H), 3.47 (d, J=5.7Hz, 1H), 3.95-4.08 (m, 2H), 4.24 (dd, J=13.9, 9.0 Hz, 1H), 4.52 (dd,J=13.8, 2.3 Hz, 1H), 7.32-7.50 (m, 6H), 7.59-7.66 (m, 1H), 7.74 (dd,J=7.7, 0.9 Hz, 1H)

Reference Example 794′-{[4-(2-{[tert-butyl(dimethyl)silyl]oxy}-2-cyclohexylethyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

To a solution (15 mL) of4′-{[4-(2-cyclohexyl-2-hydroxyethyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.64 g) in tetrahydrofuran were added 2,6-lutidine (0.22 mL) andtert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.43 mL) at 0° C.The reaction mixture was stirred at 0° C. for 3 hr, diluted with ethylacetate, washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.52 g,75%).

¹H NMR (300 MHz, CHLOROFORM-d) δ −0.48 (s, 3H), −0.06 (s, 3H), 0.74 (s,9H), 1.05 (t, J=7.3 Hz, 3H), 1.12-1.24 (m, 4H), 1.62-1.92 (m, 8H), 2.42(s, 3H), 2.92-3.09 (m, 2H), 4.01 (s, 2H), 4.08-4.22 (m, 3H), 4.31-4.41(m, 1H), 7.33-7.51 (m, 6H), 7.58-7.67 (m, 1H), 7.71-7.78 (m, 1H)

Reference Example 804′-formyl-3′-(trifluoromethyl)biphenyl-2-carbonitrile

A mixture of 4-bromo-2-(trifluoromethyl)benzaldehyde (9 g),2-cyano-phenylboric acid (9.5 g),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (2.9 g),tetrabutylammonium bromide (1.15 g), 2M aqueous sodium carbonatesolution (30 mL) and toluene (100 mL) was stirred at 100° C. overnightunder an argon atmosphere. The reaction mixture was diluted with ethylacetate, washed with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (3.2 g, 32%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 7.54-7.63 (m, 2H), 7.69-7.80 (m, 1H),7.81-7.89 (m, 1H), 7.89-7.97 (m, 2H), 8.27 (d, J=7.9 Hz, 1H), 10.46 (s,1H)

Reference Example 814′-(hydroxymethyl)-3′-(trifluoromethyl)biphenyl-2-carbonitrile

To a solution (50 mL) of4′-formyl-3′-(trifluoromethyl)biphenyl-2-carbonitrile (3.2 g) inmethanol was added sodium borohydride (0.66 g), and the mixture wasstirred at room temperature for 1 hr. After evaporation of the solventunder reduced pressure, the residue was extracted with water and ethylacetate. The obtained ethyl acetate layer was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (3.1 g, 95%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 4.97 (s, 2H), 7.46-7.56 (m, 2H),7.65-7.73 (m, 1H), 7.77-7.84 (m, 3H), 7.87-7.93 (m, 1H)

Reference Example 82 ethyl2-{[2′-cyano-3-(trifluoromethyl)biphenyl-4-yl]methyl}-3-oxohexanoate

A mixture of4′-(hydroxymethyl)-3′-(trifluoromethyl)biphenyl-2-carbonitrile (3.1 g),carbon tetrabromide (4.2 g), triphenylphosphine (3.4 g) and acetonitrile(200 mL) was stirred at room temperature for 16 hr. The reaction mixturewas diluted with ethyl acetate, and filtered through a silica gelcolumn. The filtrate was concentrated and the obtained residue wasdissolved in tetrahydrofuran (30 mL), and the mixture was added to amixture of ethyl 3-oxohexanoate (3.7 g), sodium hydride (0.6 g) andtetrahydrofuran (70 mL) stirred at 0° C. for 30 min in advance. Thereaction mixture was stirred at room temperature for 16 hr, 1 Nhydrochloric acid (50 mL) was added, and the solvent was evaporatedunder reduced pressure, and the residue was extracted with ethylacetate, and the obtained ethyl acetate layer was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as apale-yellow oil (1.1 g, 24%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.89 (t, J=7.3 Hz, 3H), 1.23 (t, J=7.2Hz, 3H), 1.53-1.65 (m, 2H), 2.35-2.47 (m, 1H), 2.52-2.65 (m, 1H),3.34-3.50 (m, 2H), 3.87 (dd, J=7.7, 6.6 Hz, 1H), 4.12-4.23 (m, 2H),7.43-7.54 (m, 3H), 7.63-7.72 (m, 2H), 7.75-7.82 (m, 2H)

Reference Example 835-methyl-N-(1-methylpropyl)-4H-1,2,4-triazol-3-amine

To a solution (50 mL) of 5-methyl-4H-1,2,4-triazol-3-amine (5 g) andbutan-2-one (5.5 g) in acetic acid was added sodium cyanoborohydride (16g), and the mixture was stirred at room temperature for 16 hr. Water wasadded to the reaction mixture, and the solvent was evaporated underreduced pressure. The obtained residue was poured into saturated aqueoussodium hydrogen carbonate, and the mixture was extracted with a mixedsolvent of ethyl acetate and isopropyl alcohol (3:1). The obtainedextract was dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure to give the title compound as acolorless solid (4.8 g, 61%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (t, J=7.4 Hz, 3H), 1.06 (d, J=6.4 Hz,3H), 1.29-1.58 (m, 2H), 2.07 (s, 3H), 3.28-3.45 (m, 1H), 5.81 (br. s.,1H), 11.70 (br. s., 1H)

Reference Example 84 5-(methoxymethyl)-4H-1,2,4-triazol-3-amine

A mixture of methoxyacetic acid (15 g), aminoguanidine sulfate (21 g)and 1,2,4-trichlorobenzene (20 mL) was stirred at 200° C. for 24 hr. Thereaction mixture was poured into saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with n-butanol. The obtainedn-butanol layer was concentrated, and the residue was purified by silicagel column chromatography to give the title compound as a colorlesssolid (15 g, 75%).

¹H NMR (300 MHz, DMSO-d₆) δ 3.24 (s, 3H), 4.16 (s, 2H), 5.81 (br. s.,2H), 11.95 (br. s., 1H)

Reference Example 855-(methoxymethyl)-N-(1-methylpropyl)-4H-1,2,4-triazol-3-amine

To a solution (5 mL) of 5-(methoxymethyl)-4H-1,2,4-triazol-3-amine (0.3g) and butan-2-one (0.25 mL) in acetic acid was added sodiumcyanoborohydride (0.6 g), and the mixture was stirred at roomtemperature for 16 hr. Water was added to the reaction mixture, and thesolvent was evaporated under reduced pressure. The obtained residue waspoured into saturated aqueous sodium hydrogen carbonate, and the mixturewas extracted with a mixed solvent of ethyl acetate and isopropylalcohol (3:1). The obtained extract was dried over anhydrous sodiumsulfate, and the solvent was evaporated under reduced pressure to givethe title compound as a colorless solid (0.2 g, 45%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.85 (t, J=7.4 Hz, 3H), 1.08 (d, J=6.6 Hz,3H), 1.34-1.57 (m, 2H), 3.25 (s, 3H), 3.34-3.46 (m, 1H), 4.14 (s, 2H),5.21-6.29 (m, 1H), 11.74-12.79 (m, 1H)

Reference Example 864′-{[2-(methoxymethyl)-4-(1-methylpropyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate(0.75 g) and5-(methoxymethyl)-N-(1-methylpropyl)-4H-1,2,4-triazol-3-amine (0.2 g)was stirred at 250° C. for 15 min under microwave irradiation. Theobtained reaction mixture was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.2 g,41%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.86 (t, J=7.44 Hz, 3H) 1.03 (t, J=7.35Hz, 3H) 1.55-1.63 (m, 3H) 1.65-1.78 (m, 2H) 1.89-2.03 (m, 1H) 2.18-2.33(m, 1H) 2.95-3.05 (m, 2H) 3.50 (s, 3H) 4.02 (s, 2H) 4.56 (s, 2H)5.09-5.20 (m, 1H) 7.31-7.51 (m, 6H) 7.58-7.66 (m, 1H) 7.74 (d, J=7.54Hz, 1H)

Reference Example 874′-{[2-methyl-5-oxo-7-propyl-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.91 g), 3-bromo-1,1,1-trifluoropropan-2-ol (1.2 mL), cesium carbonate(3.8 g) and N,N-dimethylacetamide (20 mL) was stirred at 100° C. for 4hr. The reaction mixture was diluted with ethyl acetate, washed with 5%aqueous potassium hydrogensulfate solution and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.76 g, 65%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.3 Hz, 3H), 1.66-1.81 (m,2H), 2.44 (s, 3H), 2.97-3.07 (m, 2H), 4.01 (s, 2H), 4.36-4.46 (m, 1H),4.49-4.59 (m, 1H), 4.62-4.73 (m, 1H), 4.82 (d, J=6.8 Hz, 1H), 7.31-7.52(m, 6H), 7.56-7.68 (m, 1H), 7.74 (dd, J=7.7, 0.9 Hz, 1H)

Reference Example 883′-fluoro-4′-{[2-methyl-5-oxo-7-propyl-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of ethyl2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (1 g) and5-methyl-N-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-amine (0.25 g)was stirred at 250° C. for 15 min under microwave irradiation. Theobtained reaction mixture was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.43 g,65%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.05 (t, J=7.3 Hz, 3H) 1.58-1.77 (m,4H) 2.44 (s, 3H) 2.93-3.10 (m, 4H) 3.56 (t, J=11.9 Hz, 2H) 4.00 (s, 2H)4.06-4.19 (m, 2H) 5.17-5.31 (m, 1H) 7.20-7.28 (m, 2H) 7.32-7.51 (m, 3H)7.60-7.69 (m, 1H) 7.72-7.81 (m, 1H)

Reference Example 89N-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-amine

To a solution (70 mL) of 1H-1,2,4-triazol-3-amine (3.7 g) andtetrahydro-4H-pyran-4-one (5.2 g) in acetic acid was added sodiumcyanoborohydride (14 g), and the mixture was stirred at room temperaturefor 16 hr. Water was added to the reaction mixture, and the solvent wasevaporated under reduced pressure. The obtained residue was poured intosaturated aqueous sodium hydrogen carbonate, and the mixture wasextracted with a mixed solvent of ethyl acetate and isopropyl alcohol(3:1). The obtained extract was dried over anhydrous sodium sulfate, andthe solvent was evaporated under reduced pressure to give the titlecompound as a colorless solid (0.92 g, 10%).

¹H NMR (300 MHz, DMSO-d₆) δ 1.32-1.51 (m, 2H) 1.76-1.91 (m, 2H)3.27-3.55 (m, 4H) 3.78-3.91 (m, 2H) 5.57-6.60 (m, 1H) 7.28-8.11 (m, 1H)11.97-12.91 (m, 1H)

Reference Example 904′-{[5-oxo-7-propyl-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (1g) and N-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-amine (0.25 g)was stirred at 250° C. for 15 min under microwave irradiation. Theobtained reaction mixture was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.3 g,44%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.07 (t, J=7.3 Hz, 3H), 1.61-1.78 (m,4H), 2.92-3.08 (m, 4H), 3.48-3.60 (m, 2H), 4.02 (s, 2H), 4.08-4.16 (m,2H), 5.24-5.36 (m, 1H), 7.35-7.51 (m, 6H), 7.59-7.67 (m, 1H), 7.75 (dd,J=7.7, 0.9 Hz, 1H), 7.93 (s, 1H)

Reference Example 91N-(2-methoxycyclohexyl)-5-methyl-4H-1,2,4-triazol-3-amine

To a solution (50 mL) of 5-methyl-4H-1,2,4-triazol-3-amine (2.5 g) and2-methoxycyclohexanone (3.9 g) in acetic acid was added sodiumcyanoborohydride (8.1 g), and the mixture was stirred at roomtemperature for 16 hr. Water was added to the reaction mixture, and thesolvent was evaporated under reduced pressure. The obtained residue waspoured into saturated aqueous sodium hydrogen carbonate, and the mixturewas extracted with a mixed solvent of ethyl acetate and isopropylalcohol (3:1). The obtained extract was dried over anhydrous sodiumsulfate, and the solvent was evaporated under reduced pressure to givethe title compound as a colorless solid (2.8 g, 51%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.30-2.03 (m, 9H) 2.30 (s, 3H) 3.34 (s,3H) 3.44-3.51 (m, 1H) 3.56-3.67 (m, 1H) 4.74 (d, J=8.0 Hz, 1H)

Reference Example 924′-{[4-(2-methoxycyclohexyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate(0.83 g) and N-(2-methoxycyclohexyl)-5-methyl-4H-1,2,4-triazol-3-amine(0.25 g) was stirred at 250° C. for 15 min under microwave irradiation.The obtained reaction mixture was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.27 g,46%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.04 (t, J=7.4 Hz, 3H) 1.32-2.14 (m,9H) 2.41-2.47 (m, 3H) 2.95-3.04 (m, 2H) 3.17 (s, 3H) 3.38-3.52 (m, 1H)3.73 (br. s., 1H) 3.91-4.09 (m, 2H) 4.85-4.94 (m, 1H) 7.33-7.50 (m, 6H)7.55-7.66 (m, 1H) 7.74 (dd, J=7.7, 0.9 Hz, 1H)

Reference Example 934′-{[4-(2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylpropyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

To a solution (50 mL) of 5-methyl-4H-1,2,4-triazol-3-amine (1.8 g) and3-{[tert-butyl(dimethyl)silyl]oxy}butan-2-one (4.4 g) in acetic acid wasadded sodium cyanoborohydride (5.8 g), and the mixture was stirred atroom temperature for 16 hr. Water was added to the reaction mixture, andthe solvent was evaporated under reduced pressure. The obtained residuewas poured into saturated aqueous sodium hydrogen carbonate, and themixture was extracted with a mixed solvent of ethyl acetate andisopropyl alcohol (3:1). The extract was dried over anhydrous sodiumsulfate, and the solvent was evaporated under reduced pressure. Amixture of the obtained residue and ethyl2-{[2′-cyano-3-(trifluoromethyl)biphenyl-4-yl]methyl}-3-oxohexanoate(2.3 g) was stirred at 250° C. for 15 min under microwave irradiation.The obtained reaction mixture was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.27 g,14%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.10 (s, 3H), 0.12 (s, 3H), 0.85-1.08(m, 15H), 1.54-1.76 (m, 5H), 2.36-2.47 (m, 4H), 2.91-3.00 (m, 2H), 4.01(s, 2H), 4.64-4.77 (m, 1H), 7.30-7.54 (m, 6H), 7.59-7.67 (m, 1H),7.72-7.78 (m, 1H)

Reference Example 943′-fluoro-4′-{[4-(2-methoxy-1-methylethyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of ethyl2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (1 g) andN-(2-methoxy-1-methylethyl)-5-methyl-4H-1,2,4-triazol-3-amine (0.25 g)was stirred at 250° C. for 20 min under microwave irradiation. Theobtained reaction mixture was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.28 g,40%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.04 (t, J=7.3 Hz, 3H) 1.52-1.60 (m,5H) 1.62-1.75 (m, 2H) 2.43 (s, 3H) 2.91-3.01 (m, 2H) 3.31 (s, 3H) 3.59(dd, J=10.1, 5.2 Hz, 1H) 4.01 (s, 1H) 4.34 (t, J=9.8 Hz, 1H) 5.36-5.51(m, 1H) 7.20-7.34 (m, 4H) 7.40-7.49 (m, 2H) 7.60-7.67 (m, 1H) 7.72-7.77(m, 1H)

Reference Example 955-methyl-N-(tetrahydro-2H-thiopyran-4-yl)-4H-1,2,4-triazol-3-amine

To a solution (50 mL) of 5-methyl-4H-1,2,4-triazol-3-amine (2.5 g) andtetrahydro-4H-thiopyran-4-one (3.6 g) in acetic acid was added sodiumcyanoborohydride (8.1 g), and the mixture was stirred at roomtemperature for 16 hr. Water was added to the reaction mixture, and thesolvent was evaporated under reduced pressure. The obtained residue waspoured into saturated aqueous sodium hydrogen carbonate, and the mixturewas extracted with a mixed solvent of ethyl acetate and isopropylalcohol (3:1). The obtained extract was dried over anhydrous sodiumsulfate, and the solvent was evaporated under reduced pressure to givethe title compound as a colorless solid (2.4 g, 48%).

¹H NMR (300 MHz, DMSO-d₆) δ 1.44-1.59 (m, 2H), 1.98-2.21 (m, 5H),2.54-2.67 (m, 4H), 3.21-3.34 (m, 1H), 5.44-6.42 (m, 1H), 11.53-12.35 (m,1H)

Reference Example 963′-fluoro-4′-{[2-methyl-5-oxo-7-propyl-4-(tetrahydro-2H-thiopyran-4-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of ethyl2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (1.5 g) and5-methyl-N-(tetrahydro-2H-thiopyran-4-yl)-4H-1,2,4-triazol-3-amine (0.4g) was stirred at 250° C. for 20 min under microwave irradiation. Theobtained reaction mixture was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.54 g,27%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.05 (t, J=7.4 Hz, 3H), 1.63-1.77 (m,2H), 1.98-2.07 (m, 2H), 2.44 (s, 3H), 2.66-2.80 (m, 2H), 2.84-3.13 (m,6H), 3.99 (s, 2H), 4.88-5.06 (m, 1H), 7.20-7.30 (m, 2H), 7.35 (t, J=7.8Hz, 1H), 7.41-7.51 (m, 2H), 7.60-7.67 (m, 1H), 7.75 (d, J=7.9 Hz, 1H)

Reference Example 973′-fluoro-4′-{[5-oxo-7-propyl-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of ethyl2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (1.1 g) andN-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-amine (0.25 g) wasstirred at 250° C. for 20 min under microwave irradiation. The obtainedreaction mixture was purified by silica gel column chromatography togive the title compound as a colorless solid (0.57 g, 81%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.07 (t, J=7.4 Hz, 3H), 1.62-1.79 (m,4H), 2.90-3.10 (m, 4H), 3.55 (td, J=12.0, 1.8 Hz, 2H), 4.03 (s, 2H),4.08-4.17 (m, 2H), 5.30 (tt, J=12.2, 4.1 Hz, 1H), 7.23-7.28 (m, 2H),7.36-7.51 (m, 3H), 7.63 (dd, J=7.5, 1.1 Hz, 1H), 7.75 (d, J=0.9 Hz, 1H),7.93 (s, 1H)

Reference Example 98 tert-butyl2-[(trans-4-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]propanoate

To a mixture of3′-fluoro-4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(233 g), tert-butyl 2-bromopropanoate (301 g), toluene (1.7 L) and 50%sodium hydroxide (1.7 L) was added tetrabutylammonium hydrogen sulfate(16.3 g), and the mixture was stirred with the internal temperaturemaintained below 30° C. for 16 hr. Water (1 L) was slowly added underice-cooling, and phases were separated. The aqueous layer was extractedwith tetrahydrofuran (1.0 L). The combined extracts were successivelywashed with 3M hydrochloric acid (1 L) and brine (1 L), dried overanhydrous magnesium sulfate, and concentrated. The residue was purifiedby silica gel column chromatography to give the title compound as anamorphous pale-yellow solid (283 g, 96%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.3 Hz, 3H), 1.20-1.47 (m, 14H),1.56-1.75 (m, 4H), 1.99-2.17 (m, 2H), 2.46-2.64 (m, 2H), 2.92-3.02 (m,2H), 3.27-3.39 (m, 1H), 3.95-4.08 (m, 3H), 4.81-4.95 (m, 1H), 7.11-7.67(m, 5 H), 7.75-7.84 (m, 1H), 7.96 (d, J=7.7 Hz, 1H), 8.20 (s, 1H)

Reference Example 994′-({4-[(2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)-3′-fluorobiphenyl-2-carbonitrile

A mixture of ethyl2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (2.1 g) andN-[(2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]-3-methyl-1H-1,2,4-triazol-5-amine(0.6 g) was stirred at 250° C. for 30 min under microwave irradiation.The obtained reaction mixture was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.33 g,23%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.05 (t, J=7.3 Hz, 3H), 1.26 (s, 3H),1.28 (s, 3H), 1.63-1.76 (m, 4H), 2.44 (s, 3H), 2.58 (q, J=12.4 Hz, 2H),2.95-3.03 (m, 2H), 3.56-3.70 (m, 2H), 4.00 (s, 2H), 5.16-5.36 (m, 1H),7.20-7.30 (m, 2H), 7.35 (t, J=7.8 Hz, 1H), 7.41-7.52 (m, 2H), 7.60-7.67(m, 1H), 7.71-7.79 (m, 1H)

Reference Example 1004′-({4-[(2R,4s,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)-3′-fluorobiphenyl-2-carbonitrile

A mixture of ethyl2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (2.1 g) andN-[(2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]-3-methyl-1H-1,2,4-triazol-5-amine(0.6 g) was stirred at 250° C. for 30 min under microwave irradiation.The obtained reaction mixture was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.052 g,4%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.04 (t, J=7.4 Hz, 3H), 1.23 (s, 3H),1.25 (s, 3H), 1.63-1.76 (m, 4H), 2.43 (s, 3H), 2.47-2.58 (m, 2H),2.93-3.01 (m, 2H), 4.01 (s, 2H), 4.19-4.32 (m, 2H), 5.33-5.47 (m, 1H),7.21-7.27 (m, 2H), 7.34 (t, J=7.7 Hz, 1H), 7.40-7.50 (m, 2H), 7.59-7.68(m, 1H), 7.73-7.79 (m, 1H)

Reference Example 101N-(tetrahydro-2H-pyran-3-yl)-4H-1,2,4-triazol-3-amine

A mixture of tetrahydro-2H-pyran-3-ol (2.7 g), pyridinium dichromate (15g), molecular sieves 4A (15 g) and tetrahydrofuran (200 mL) was stirredat room temperature for 3 hr. The reaction solution was diluted withdiethyl ether (200 mL), the insoluble material was filtered off throughsilica gel, and the filtrate was concentrated. The obtained residue wasdissolved in acetic acid (20 mL), 1H-1,2,4-triazol-3-amine (1.1 g) andsodium cyanoborohydride (4.2 g) were added, and the mixture was stirredat room temperature for 16 hr. Water was added to the reaction mixture,and the solvent was evaporated under reduced pressure. The obtainedresidue was poured into saturated aqueous sodium hydrogen carbonate, andthe mixture was extracted with a mixed solvent of ethyl acetate andisopropyl alcohol (3:1). The obtained extract was dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure togive the title compound as a colorless solid (0.19 g, 9%).

¹H NMR (300 MHz, DMSO-d₆) δ 1.33-1.57 (m, 2H), 1.61-1.74 (m, 1H),1.88-2.02 (m, 1H), 2.95-3.14 (m, 1H), 3.32 (s, 1H), 3.35-3.49 (m, 1H),3.64-3.75 (m, 1H), 3.77-3.91 (m, 1H), 5.37-6.61 (m, 1H), 7.21-8.18 (m,1H), 11.88-12.86 (m, 1H)

Reference Example 1023′-fluoro-4′-{[5-oxo-7-propyl-4-(tetrahydro-2H-pyran-3-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of ethyl2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (0.42 g) andN-(tetrahydro-2H-pyran-3-yl)-4H-1,2,4-triazol-3-amine (0.1 g) wasstirred at 250° C. for 20 min under microwave irradiation. The obtainedreaction mixture was purified by silica gel column chromatography togive the title compound as a colorless solid (0.17 g, 60%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.3 Hz, 3H), 1.64-1.97 (m,5H), 2.75-2.93 (m, 1H), 2.99-3.08 (m, 2H), 3.47-3.56 (m, 1H), 3.85-4.04(m, 4H), 4.45 (t, J=10.6 Hz, 1H), 5.17-5.30 (m, 1H), 7.23-7.29 (m, 2H),7.34-7.50 (m, 3H), 7.60-7.69 (m, 1H), 7.72-7.78 (m, 1H), 7.91 (s, 1H)

Reference Example 103N-(1,4-dioxaspiro[4.5]dec-8-yl)-5-methyl-4H-1,2,4-triazol-3-amine

Sodium triacetoxyborohydride (32.4 g) was gradually added to a solution(150 mL) of 5-methyl-4H-1,2,4-triazol-3-amine (10.0 g) and1,4-cyclohexanedione monoethyleneketal (19.1 g) in acetic acid. Themixture was stirred at room temperature for 16 hr, water was added tothe reaction mixture, and the mixture was concentrated under reducedpressure. The obtained residue was poured into saturated aqueous sodiumhydrogen carbonate, and the mixture was extracted 3 times with a mixedsolvent of ethyl acetate and isopropyl alcohol (3:1). The obtainedextract was dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure, and the residue was solidified withdiisopropyl ether, and the solid was collected by filtration, and driedto give the title compound (15.6 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.37-1.57 (m, 4H), 1.59-1.73 (m, 2H),1.74-1.90 (m, 2H), 2.06 (s, 3H), 3.84 (s, 4H), 6.03 (br. s., 1H), 11.88(br. s., 1H)

Reference Example 1044′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile

A mixture of ethyl2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (1.5 g) andN-(1,4-dioxaspiro[4.5]dec-8-yl)-5-methyl-4H-1,2,4-triazol-3-amine (0.5g) was stirred at 250° C. for 20 min under microwave irradiation. Theobtained reaction mixture was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.32 g,28%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.4 Hz, 3H), 1.64-1.97 (m,5H), 2.74-2.94 (m, 1H), 2.96-3.07 (m, 2H), 3.51 (td, J=11.5, 2.8 Hz,1H), 3.84-4.03 (m, 6H), 3.84-4.03 (m, 4H), 4.45 (t, J=10.6 Hz, 1H),5.15-5.31 (m, 1H), 7.34-7.53 (m, 6H), 7.58-7.68 (m, 1H), 7.75 (d, J=8.0Hz, 1H), 7.91 (s, 1H)

Reference Example 1054′-{[5-oxo-7-propyl-4-(tetrahydro-2H-pyran-3-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate(0.37 g) and N-(tetrahydro-2H-pyran-3-yl)-4H-1,2,4-triazol-3-amine(0.088 g) was stirred at 250° C. for 20 min under microwave irradiation.The obtained reaction mixture was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.15 g,63%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.4 Hz, 3H), 1.64-1.97 (m,J=15.4, 7.6, 7.4, 7.4 Hz, 5H), 2.74-2.94 (m, 1H), 2.96-3.07 (m, 2H),3.51 (td, J=11.5, 2.8 Hz, 1H), 3.84-4.03 (m, 6H), 3.84-4.03 (m, 4H),4.45 (t, J=10.6 Hz, 1H), 5.15-5.31 (m, 1H), 7.34-7.53 (m, 6H), 7.58-7.68(m, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.91 (s, 1H)

Reference Example 1064′-{[5-oxo-7-butyl-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate(1.3 g) and N-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-amine (0.3g) was stirred at 250° C. for 15 min under microwave irradiation. Theobtained reaction mixture was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.52 g,62%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.96 (t, J=7.2 Hz, 3H), 1.41-1.54 (m,2H), 1.59-1.73 (m, 4H), 2.91-3.10 (m, 4H), 3.54 (t, J=11.0 Hz, 2H), 4.02(s, 2H), 4.07-4.17 (m, 2H), 5.21-5.40 (m, 1H), 7.34-7.51 (m, 6H),7.58-7.68 (m, 1H), 7.75 (d, J=6.8 Hz, 1H), 7.93 (s, 1H)

Reference Example 1073′-fluoro-4′-({4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(retention time: short)

tert-Butyl2-[(trans-4-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]propanoate(548 g) was dissolved in tetrahydrofuran (2.7 L), and methylmagnesiumbromide (1.0 M tetrahydrofuran solution, 3.5 L) was added with theinternal temperature maintained below 10° C. The reaction mixture wasstirred at the same temperature for 1 hr, and partitioned amongsaturated aqueous ammonium chloride solution (600 mL), water (600 mL)and ethyl acetate (500 mL). The aqueous layer was extracted with ethylacetate (1 L). The combined extracts were washed with saturated brine (1L), dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The resulting residue was purified by silica gelcolumn chromatography to give the title compound as a racemate (428 g,84%).

The racemate (500 g) obtained by the above-mentioned method was resolvedusing a chiral column to give the title compound as a colorless solid(199 g, 99% ee, 40%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90-1.11 (m, 12H), 1.16-1.39 (m, 2H),1.54-1.75 (m, 4H), 1.94-2.14 (m, 2H), 2.47-2.68 (m, 2H), 2.91-3.02 (m,2H), 3.24 (q, J=6.0 Hz, 1H), 3.30-3.44 (m, 1H), 3.97 (s, 2H), 4.06 (s,1H), 4.80-4.97 (m, 1H), 7.26-7.39 (m, 2H), 7.41-7.50 (m, 1H), 7.54-7.67(m, 2H), 7.75-7.83 (m, 1H), 7.95 (d, J=7.6 Hz, 1H), 8.20 (s, 1H)

Analysis of Enantiomeric Excess

column: CHIRALPAK IA 4.6 mm ID×250 mL

mobile phase: n-Hex/IPA=90/10 (v/v)

flow rate: 1.0 mL/min

temperature: 40° C.

detection: UV 254 nm

concentration: 1 mg/mL (n-Hex/IPA=90/10)

injection volume: 0.01 mL

retention time: 19.5 min

Reference Example 1084′-({4-[(2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (2.5g) andN-[(2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]-1H-1,2,4-triazol-5-amine(0.7 g) was stirred at 250° C. for 20 min under microwave irradiation.The obtained reaction mixture was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.53 g,31%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.3 Hz, 3H), 1.27 (t, J=7.2Hz, 6H), 1.65-1.78 (m, 4H), 2.46-2.64 (m, 2H), 2.97-3.10 (m, 2H),3.56-3.72 (m, 2H), 4.02 (s, 2H), 5.24-5.39 (m, 1H), 7.32-7.53 (m, 6H),7.59-7.67 (m, 1H), 7.75 (dd, J=7.6, 0.8 Hz, 1H), 7.93 (s, 1H)

Reference Example 1094′-({4-[(2R,4s,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (2.5g) andN-[(2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]-1H-1,2,4-triazol-5-amine(0.7 g) was stirred at 250° C. for 20 min under microwave irradiation.The obtained reaction mixture was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.098 g,6%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.4 Hz, 3H), 1.24 (d, J=6.0Hz, 6H), 1.64-1.80 (m, 4H), 2.47-2.64 (m, 2H), 2.97-3.07 (m, 2H), 4.03(s, 2H), 4.20-4.34 (m, 2H), 5.40-5.53 (m, 1H), 7.33-7.53 (m, 6H),7.58-7.68 (m, 1 H), 7.75 (dd, J=7.7, 0.9 Hz, 1H), 7.92 (s, 1H)

Reference Example 1104′-{[5-oxo-7-propyl-4-(tetrahydrofuran-3-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of tetrahydrofuran-3-ol (5 g), pyridinium dichromate (32 g),molecular sieves 4A (32 g) and tetrahydrofuran (400 mL) was stirred atroom temperature for 3 hr. The reaction solution was diluted withdiethyl ether (400 mL), the insoluble material was filtered off throughsilica gel, and the filtrate was concentrated. The obtained residue wasdissolved in acetic acid (30 mL), 1H-1,2,4-triazol-3-amine (2.4 g) andsodium cyanoborohydride (9 g) were added, and the mixture was stirred atroom temperature for 16 hr. Water was added to the reaction mixture, andthe solvent was evaporated under reduced pressure. The obtained residuewas poured into saturated aqueous sodium hydrogen carbonate, and themixture was extracted with a mixed solvent of ethyl acetate andisopropyl alcohol (3:1). The obtained extract was dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure. Amixture of the obtained residue and ethyl2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (1.8 g) was stirred at250° C. for 20 min under microwave irradiation. The obtained reactionmixture was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.18 g, 1%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.07 (t, J=7.2 Hz, 3H) 1.65-1.80 (m,2H) 2.22-2.41 (m, 1H) 2.51-2.68 (m, 1H) 2.98-3.09 (m, 2H) 3.89-4.13 (m,5H) 4.29-4.45 (m, 1H) 5.77-5.91 (m, 1H) 7.34-7.51 (m, 6H) 7.59-7.67 (m,1H) 7.71-7.79 (m, 1H) 7.95 (s, 1H)

Reference Example 111N-(2-methyltetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-amine

A mixture of 2-methyltetrahydro-2H-pyran-4-ol (3.5 g), pyridiniumdichromate (34 g), molecular sieves 4A (20 g) and tetrahydrofuran (300mL) was stirred at room temperature for 3 hr. The reaction solution wasdiluted with diethyl ether (300 mL), the insoluble material was filteredoff through silica gel, and the filtrate was concentrated. The obtainedresidue was dissolved in acetic acid (30 mL), 1H-1,2,4-triazol-3-amine(1.7 g) and sodium cyanoborohydride (8.5 g) were added, and the mixturewas stirred at room temperature for 16 hr. Water was added to thereaction mixture, and the solvent was evaporated under reduced pressure.The obtained residue was poured into saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with a mixed solvent of ethylacetate and isopropyl alcohol (3:1). The obtained extract was dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (2 g,54%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.99-1.15 (m, 3H), 1.21-1.94 (m, 3H),3.28-3.90 (m, 4H), 6.39-6.80 (m, 1H), 7.21-8.09 (m, 1H), 11.83-12.88 (m,1H)

Reference Example 1124′-{[4-(2-methyltetrahydro-2H-pyran-4-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (1.2g) and N-(2-methyltetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-amine(0.3 g) was stirred at 250° C. for 20 min under microwave irradiation.The obtained reaction mixture was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.43 g,56%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.3 Hz, 3H) 1.21-1.83 (m,9H) 2.52-3.19 (m, 4H) 3.53-4.45 (m, 4H) 5.23-5.65 (m, 1H) 7.34-7.53 (m,6H) 7.59-7.67 (m, 1H) 7.75 (d, J=7.7 Hz, 1H) 7.93 (s, 1H)

Reference Example 1134′-{[7-butyl-4-(2-methyltetrahydro-2H-pyran-4-yl)-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate(1.2 g) andN-(2-methyltetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-amine (0.3 g)was stirred at 250° C. for 20 min under microwave irradiation. Theobtained reaction mixture was purified by silica gel columnchromatography to give the title compound as a mixture of 4 kinds ofisomers (0.49 g, 62%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.95 (t, J=7.3 Hz, 3H), 1.23-1.29,1.38-1.42 (m, combined 3H), 1.42-1.78 (m, 6H), 2.55-2.71, 2.78-3.19 (m,combined 4H), 3.54-3.70, 3.84-3.91 (m, combined 2H), 4.02 (s, 2H),4.08-4.17, 4.33-4.45 (m, combined 1H), 5.23-5.40, 5.51-5.66 (m, combined1H), 7.34-7.53 (m, 6H), 7.59-7.67 (m, 1H), 7.75 (dd, J=7.7, 0.9 Hz, 1H),7.94 (s, 1H)

The obtained isomer mixture was subjected to the following conditions togive 4 kinds of single isomers [tR1 (148 mg), tR2 (57 mg), tR3 (141 mg),tR4 (58 mg), retention time arranged in the ascending order].

column: CHIRALPAK AD (IL001) 50 mm ID×500 mL

mobile phase: n-Hex/IPA=900/100 (v/v)

flow rate: 75 ml/min

temperature: 30° C.

detection: UV 220 nm

concentration: 0.5 mg/ml (n-Hex/IPA=900/100)

injection volume: 50 ml

load: 25 mg

cycle time: 95 min

Reference Example 1144′-{[7-butyl-2-methyl-5-oxo-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate(1.2 g) and5-methyl-N-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-amine (0.3 g)was stirred at 250° C. for 20 min under microwave irradiation. Theobtained reaction mixture was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.52 g,66%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.95 (t, J=7.4 Hz, 3H) 1.38-1.52 (m,2H) 1.58-1.70 (m, 4H) 2.44 (s, 3H) 2.93-3.10 (m, 4H) 3.53 (t, J=12.2 Hz,2H) 3.99 (s, 2H) 4.05-4.15 (m, 2H) 5.17-5.33 (m, 1H) 7.32-7.52 (m, 6H)7.57-7.66 (m, 1H) 7.75 (dd, J=7.7, 0.9 Hz, 1H)

Reference Example 115N-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-amine

A mixture of 2,2-dimethyltetrahydro-2H-pyran-4-ol (5 g), pyridiniumdichromate (22 g), molecular sieves 4A (22 g) and tetrahydrofuran (200mL) was stirred at room temperature for 3 hr. The reaction solution wasdiluted with diethyl ether (200 mL), the insoluble material was filteredoff through silica gel, and the filtrate was concentrated. The obtainedresidue was dissolved in acetic acid (30 mL), 1H-1,2,4-triazol-3-amine(2.2 g) and sodium cyanoborohydride (11 g) were added, and the mixturewas stirred at room temperature for 16 hr. Water was added to thereaction mixture, and the solvent was evaporated under reduced pressure.The obtained residue was poured into saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with a mixed solvent of ethylacetate and isopropyl alcohol (3:1). The obtained extract was dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (1.8 g,60%).

¹H NMR (300 MHz, DMSO-d₆) δ 1.09-1.33 (m, 8H), 1.71-1.88 (m, 2H),3.51-3.70 (m, 3H), 5.42-6.47 (m, 1H), 7.22-8.07 (m, 1H), 11.97-12.81 (m,1H)

Reference Example 1164′-{[4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate(0.89 g) andN-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-amine (0.25g) was stirred at 250° C. for 20 min under microwave irradiation. Theobtained reaction mixture was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.41 g,67%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.3 Hz, 3H), 1.32 (s, 3H),1.37 (s, 3H), 1.54-1.79 (m, 5H), 2.78 (t, J=12.6 Hz, 1H), 2.84-3.11 (m,3H), 3.75-3.96 (m, 2H), 4.03 (s, 2H), 5.43-5.62 (m, 1H), 7.33-7.52 (m,6H), 7.58-7.66 (m, 1H), 7.75 (d, J=7.7 Hz, 1H), 7.94 (s, 1H)

Reference Example 1174′-{[7-butyl-4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate(0.89 g) andN-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-amine (0.25g) was stirred at 250° C. for 20 min under microwave irradiation. Theobtained reaction mixture was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.45 g,71%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.95 (t, J=7.2 Hz, 3H) 1.32 (s, 3H)1.36 (s, 3H) 1.40-1.54 (m, 2H) 1.56-1.70 (m, 4H) 2.78 (t, J=12.6 Hz, 1H)2.86-3.09 (m, 3H) 3.74-3.96 (m, 2H) 4.02 (s, 2H) 5.45-5.59 (m, 1H)7.33-7.51 (m, 6H) 7.57-7.66 (m, 1H) 7.75 (d, J=7.7 Hz, 1H) 7.94 (s, 1H)

Reference Example 1184′-{[7-butyl-2-methyl-5-oxo-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile

A mixture of methyl2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxoheptanoate (1 g) and5-methyl-N-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-amine (0.25 g)was stirred at 250° C. for 20 min under microwave irradiation. Theobtained reaction mixture was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.49 g,72%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.94 (t, J=7.3 Hz, 3H), 1.38-1.53 (m,2H), 1.57-1.70 (m, 4H), 2.44 (s, 3H), 2.93-3.11 (m, 4H), 3.55 (t, J=11.2Hz, 2H), 4.00 (s, 2H), 4.06-4.17 (m, 2H), 5.17-5.31 (m, 1H), 7.20-7.27(m, 2H), 7.32-7.49 (m, 3H), 7.61-7.70 (m, 1H), 7.76 (d, J=7.7 Hz, 1H)

Reference Example 119N-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-5-methyl-4H-1,2,4-triazol-3-amine

A mixture of 2,2-dimethyltetrahydro-2H-pyran-4-ol (5 g), pyridiniumdichromate (22 g), molecular sieves 4A (22 g) and tetrahydrofuran (200mL) was stirred at room temperature for 3 hr. The reaction solution wasdiluted with diethyl ether (200 mL), the insoluble material was filteredoff through silica gel, and the filtrate was concentrated. The obtainedresidue was dissolved in acetic acid (30 mL),5-methyl-4H-1,2,4-triazol-3-amine (2.5 g) and sodium cyanoborohydride(11 g) were added, and the mixture was stirred at room temperature for16 hr. Water was added to the reaction mixture, and the solvent wasevaporated under reduced pressure. The obtained residue was poured intosaturated aqueous sodium hydrogen carbonate, and the mixture wasextracted with a mixed solvent of ethyl acetate and isopropyl alcohol(3:1). The obtained extract was dried over anhydrous sodium sulfate, andthe solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (1.6 g, 49%).

¹H NMR (300 MHz, DMSO-d₆) δ 1.03-1.30 (m, 8H), 1.70-1.85 (m, 2H), 2.07(br.s., 3H), 3.48-3.66 (m, 3H), 5.17-6.39 (m, 1H), 11.47-12.45 (m, 1H)

Reference Example 1204′-{[4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile

A mixture of ethyl2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (0.87 g) andN-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-5-methyl-4H-1,2,4-triazol-3-amine(0.25 g) was stirred at 250° C. for 20 min under microwave irradiation.The obtained reaction mixture was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.34 g,56%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.05 (t, J=7.3 Hz, 3H), 1.32 (s, 3H),1.36 (s, 3H), 1.52-1.76 (m, 4H), 2.44 (s, 3H), 2.80 (t, J=12.6 Hz, 1H),2.90-3.06 (m, 3H), 3.73-3.95 (m, 2H), 4.01 (s, 2H), 5.40-5.56 (m, 1H),7.21-7.30 (m, 2H), 7.34 (t, J=7.7 Hz, 1H), 7.41-7.51 (m, 2H), 7.59-7.68(m, 1H), 7.75 (d, J=7.7 Hz, 1H)

Reference Example 1214′-{[7-butyl-4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-methyl-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate(0.83 g) andN-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-amine (0.25g) was stirred at 250° C. for 20 min under microwave irradiation. Theobtained reaction mixture was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.39 g,64%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.94 (t, J=7.3 Hz, 3H), 1.31 (s, 3H),1.35 (s, 3H), 1.38-1.50 (m, 2H), 1.51-1.69 (m, 4H), 2.44 (s, 3H), 2.80(t, J=12.6 Hz, 1H), 2.88-3.05 (m, 3H), 3.76-3.93 (m, 2H), 3.99 (s, 2H),5.42-5.55 (m, 1H), 7.32-7.52 (m, 6H), 7.59-7.66 (m, 1H), 7.75 (dd,J=7.7, 0.9 Hz, 1H)

Reference Example 1224′-({7-butyl-4-[(2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate(0.89 g) andN-[(2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]-1H-1,2,4-triazol-5-amine(0.25 g) was stirred at 250° C. for 20 min under microwave irradiation.The obtained reaction mixture was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.27 g,64%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.95 (t, J=7.2 Hz, 3H), 1.28 (d, J=6.2Hz, 6H), 1.38-1.54 (m, 2H), 1.57-1.75 (m, 4H), 2.56 (q, J=12.2 Hz, 2H),3.01-3.09 (m, 2H), 3.58-3.71 (m, 2H), 4.02 (s, 2H), 5.26-5.41 (m, 1H),7.34-7.52 (m, 6H), 7.58-7.66 (m, 1H), 7.75 (d, J=7.7 Hz, 1H), 7.93 (s,1H)

Reference Example 1234′-({7-butyl-4-[(2R,4s,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate(0.89 g) andN-[(2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]-1H-1,2,4-triazol-5-amine(0.25 g) was stirred at 250° C. for 20 min under microwave irradiation.The obtained reaction mixture was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.094 g,15%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.95 (t, J=7.3 Hz, 3H), 1.22-1.27 (m,6H), 1.39-1.53 (m, 2H), 1.59-1.75 (m, 2H), 2.49-2.63 (m, 2H), 2.99-3.10(m, 2H), 4.02 (s, 2H), 4.20-4.32 (m, 2H), 5.39-5.52 (m, 1H), 7.33-7.52(m, 6H), 7.58-7.67 (m, 1H), 7.75 (dd, J=7.7, 0.9 Hz, 1H), 7.92 (s, 1H)

Reference Example 124N-(1,4-dioxaspiro[4.5]dec-8-yl)-4H-1,2,4-triazol-3-amine

To a solution of 1H-1,2,4-triazol-3-amine (66.6 g) and1,4-dioxaspiro[4.5]decan-8-one (175 g) in acetic acid (1.25 L) wasgradually added sodium triacetoxyborohydride (252 g) under ice-cooling.After stirring at room temperature for 16 hr, water (1 L) was added tothe reaction mixture, and the mixture was concentrated under reducedpressure. The obtained residue was poured into saturated aqueous sodiumhydrogen carbonate (1 L). The mixture was neutralized with sodiumbicarbonate, and extracted 3 times with a mixed solvent of ethyl acetateand isopropyl alcohol (3:1, 2 L). The combined extracts were dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was solidified with diisopropyl ether (500 mL), and theresulting solid was collected by filtration, washed twice withdiisopropyl ether (250 mL), and dried to give the title compound (166 g,94%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.51-1.88 (m, 6H), 2.01-2.13 (m, 2H),3.56 (br.s., 1H), 3.96 (s, 4H), 4.53 (br. s., 1H), 7.72 (s, 1H)

Reference Example 1254′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (1.9g) and N-(1,4-dioxaspiro[4.5]dec-8-yl)-4H-1,2,4-triazol-3-amine (0.6 g)was stirred at 250° C. for 20 min under microwave irradiation. Theobtained reaction mixture was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.78 g,56%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.3 Hz, 3H), 1.64-1.97 (m,8H), 2.84-3.07 (m, 4H), 3.91-4.06 (m, 6H), 5.06-5.22 (m, 1H), 7.33-7.53(m, 6H), 7.57-7.67 (m, 1H), 7.74 (d, J=7.7 Hz, 1H), 7.96 (s, 1H)

Reference Example 1264′-{[7-butyl-4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate(1.9 g) and N-(1,4-dioxaspiro[4.5]dec-8-yl)-4H-1,2,4-triazol-3-amine(0.6 g) was stirred at 250° C. for 20 min under microwave irradiation.The obtained reaction mixture was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.75 g,53%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.95 (t, J=7.3 Hz, 3H) 1.39-1.53 (m,2H) 1.57-1.94 (m, 8H) 2.90-3.07 (m, 4H) 3.91-4.06 (m, 6H) 5.05-5.23 (m,1H) 7.34-7.52 (m, 6H) 7.57-7.68 (m, 1H) 7.75 (dd, J=7.7, 0.9 Hz, 1H)7.97 (s, 1H)

Reference Example 1275-methyl-N-(6-methyltetrahydro-2H-pyran-3-yl)-4H-1,2,4-triazol-3-amine

A mixture of 6-methyltetrahydro-2H-pyran-3-ol (2.5 g), pyridiniumdichromate (16 g), molecular sieves 4A (16 g) and tetrahydrofuran (100mL) was stirred at room temperature for 3 hr. The reaction solution wasdiluted with diethyl ether (100 mL), the insoluble material was filteredoff through silica gel, and the filtrate was concentrated. The obtainedresidue was dissolved in acetic acid (50 mL),5-methyl-4H-1,2,4-triazol-3-amine (1.4 g) and sodium cyanoborohydride (6g) were added, and the mixture was stirred at room temperature for 16hr. Water was added to the reaction mixture, and the solvent wasevaporated under reduced pressure. The obtained residue was poured intosaturated aqueous sodium hydrogen carbonate, and the mixture wasextracted with a mixed solvent of ethyl acetate and isopropyl alcohol(3:1). The obtained extract was dried over anhydrous sodium sulfate, andthe solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.04 g, 48%).

¹H NMR (300 MHz, DMSO-d₆) δ 1.03-1.11 (m, 3H), 1.16-2.30 (m, 7H),2.89-3.97 (m, 3H), 5.37-6.32 (m, 1H), 11.26-11.75 (m, 1H)

Reference Example 1284′-{[2-methyl-4-(6-methyltetrahydro-2H-pyran-3-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate(0.89 g) and5-methyl-N-(6-methyltetrahydro-2H-pyran-3-yl)-4H-1,2,4-triazol-3-amine(0.25 g) was stirred at 250° C. for 20 min under microwave irradiation.The obtained reaction mixture was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.18 g,30%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.04 (t, J=7.3 Hz, 3H), 1.21 (d, J=6.2Hz, 3H), 1.41-1.54 (m, 1H), 1.63-1.77 (m, 2H), 1.79-1.91 (m, 2H), 2.43(s, 3H), 2.79-2.99 (m, 3H), 3.58-3.69 (m, 1H), 3.82-3.90 (m, 1H), 3.98(s, 2H), 4.55 (t, J=10.6 Hz, 1H), 5.08-5.21 (m, 1H), 7.34 (d, J=8.3 Hz,2H), 7.38-7.51 (m, 4H), 7.58-7.66 (m, 1H), 7.74 (dd, J=7.7, 0.9 Hz, 1H)

Reference Example 1294′-{[5-oxo-7-pentyl-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxooctanoate(1.1 g) and5-methyl-N-(6-methyltetrahydro-2H-pyran-3-yl)-4H-1,2,4-triazol-3-amine(0.25 g) was stirred at 250° C. for 20 min under microwave irradiation.The obtained reaction mixture was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.48 g,67%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.04 (t, J=7.3 Hz, 3H), 1.21 (d, J=6.2Hz, 3H), 1.41-1.54 (m, 1H), 1.63-1.77 (m, 2H), 1.79-1.91 (m, 2H), 2.43(s, 3H), 2.79-2.99 (m, 3H), 3.58-3.69 (m, 1H), 3.82-3.90 (m, 1H), 3.98(s, 2H), 4.55 (t, J=10.6 Hz, 1H), 5.08-5.21 (m, 1H), 7.34 (d, J=8.3 Hz,2H), 7.38-7.51 (m, 4H), 7.58-7.66 (m, 1H), 7.74 (dd, J=7.7, 0.9 Hz, 1H)

Reference Example 1304′-{[7-butyl-4-(4-hydroxycyclohexyl)-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-{[7-butyl-4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.34 g), 6N hydrochloric acid (2 mL) and tetrahydrofuran (10 mL) wasstirred at 40° C. for 3 hr. The reaction mixture was diluted with ethylacetate, washed with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure. The residueobtained by silica gel column chromatography was dissolved in methanol(10 mL), sodium borohydride (0.047 g) was added, and the mixture wasstirred at room temperature for 1 hr. After evaporation of the solventunder reduced pressure, the residue was extracted with water and ethylacetate. The obtained ethyl acetate layer was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.31 g, 100%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.95 (t, J=7.3 Hz, 3H), 1.39-1.83 (m,8H), 1.93-2.17 (m, 2H), 2.65-2.82 (m, 2H), 2.90-3.08 (m, 2H), 3.75-3.89(m, 1H), 3.98-4.04 (m, 2H), 4.98-5.13 (m, 1H), 7.34-7.52 (m, 6H),7.59-7.66 (m, 1H), 7.75 (dd, J=7.7, 0.9 Hz, 1H), 7.90-7.96 (m, 1H)

Reference Example 1314′-{[7-butyl-4-(4-methoxycyclohexyl)-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

To a mixture of4′-{[7-butyl-4-(4-hydroxycyclohexyl)-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.37 g), methyl iodide (0.053 mL) and N,N-dimethylformamide (10 mL) wasadded sodium hydride (0.034 g), and the mixture was stirred at roomtemperature for 16 hr. The reaction mixture was diluted with ethylacetate, washed with 5% aqueous potassium hydrogensulfate solution andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.16 g, 42%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.95 (t, J=7.4 Hz, 3H), 1.37-1.52 (m,4H), 1.59-1.71 (m, 2H), 1.75-1.86 (m, 2H), 2.14-2.27 (m, 2H), 2.62-2.79(m, 2H), 2.99-3.08 (m, 2H), 3.27-3.39 (m, 4H), 4.01 (s, 2H), 5.00-5.14(m, 1H), 7.34-7.51 (m, 6H), 7.59-7.65 (m, 1H), 7.75 (dd, J=7.8, 1.0 Hz,1H), 7.91-7.95 (m, 1H)

Reference Example 1324′-{[2-methyl-4-(5-methyltetrahydrofuran-3-yl)-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of 2,5-anhydro-1,3-dideoxypentitol (2 g), pyridiniumdichromate (11 g), molecular sieves 4A (11 g) and tetrahydrofuran (100mL) was stirred at room temperature for 3 hr. The reaction solution wasdiluted with diethyl ether (100 mL), the insoluble material was filteredoff through silica gel, and the filtrate was concentrated. The obtainedresidue was dissolved in acetic acid (20 mL),5-methyl-4H-1,2,4-triazol-3-amine (1.2 g) and sodium cyanoborohydride(5.4 g) were added, and the mixture was stirred at room temperature for16 hr. Water was added to the reaction mixture, and the solvent wasevaporated under reduced pressure. The obtained residue was poured intosaturated aqueous sodium hydrogen carbonate, and the mixture wasextracted with a mixed solvent of ethyl acetate and isopropyl alcohol(3:1). The obtained extract was dried over anhydrous sodium sulfate, andthe solvent was evaporated under reduced pressure. A mixture of theobtained residue and ethyl2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (3.5 g) was stirred at250° C. for 20 min under microwave irradiation. The obtained reactionmixture was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.1 g, 2%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.04 (t, J=7.3 Hz, 3H) 1.33 (d, J=6.0Hz, 3H) 1.63-1.90 (m, 3H) 2.43 (s, 3H) 2.56-2.66 (m, 1H) 2.92-3.02 (m,2H) 4.00 (s, 2H) 4.06-4.22 (m, 2H) 4.64-4.77 (m, 1H) 5.67-5.81 (m, 1H)7.31-7.53 (m, 6H) 7.59-7.65 (m, 1H) 7.75 (dd, J=7.7, 0.9 Hz, 1H)

Reference Example 133N-(1-oxaspiro[4.5]dec-8-yl)-4H-1,2,4-triazol-3-amine

To a solution (70 mL) of 1H-1,2,4-triazol-3-amine (0.29 g) and1-oxaspiro[4.5]decan-8-one (0.64 g) in acetic acid was added sodiumcyanoborohydride (1.1 g), and the mixture was stirred at roomtemperature for 16 hr. Water was added to the reaction mixture, and thesolvent was evaporated under reduced pressure. The obtained residue waspoured into saturated aqueous sodium hydrogen carbonate, and the mixturewas extracted with a mixed solvent of ethyl acetate and isopropylalcohol (3:1). The obtained extract was dried over anhydrous sodiumsulfate, and the solvent was evaporated under reduced pressure. Theobtained reaction mixture was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.25 g,34%).

¹H NMR (300 MHz, DMSO-d₆) δ 1.23-1.94 (m, 12H), 3.17-3.38 (m, 1H),3.62-3.74 (m, 2H), 5.44-6.42 (m, 1H), 7.24-8.05 (m, 1H), 11.86-12.74 (m,1H)

Reference Example 1344′-{[4-(4-methoxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(2 g), 6N hydrochloric acid (20 mL) and tetrahydrofuran (30 mL) wasstirred at 70° C. for 16 hr. The reaction mixture was diluted with ethylacetate, washed with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure. The obtainedresidue was dissolved in methanol (30 mL), sodium borohydride (0.18 g)was added, and the mixture was stirred at room temperature for 1 hr.After evaporation of the solvent under reduced pressure, the residue wasextracted with water and ethyl acetate. The obtained ethyl acetate layerwas washed with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure. The residueobtained by silica gel column chromatography was dissolved inN,N-dimethylformamide (10 mL), methyl iodide (0.13 mL) and sodiumhydride (0.05 g) were added, and the mixture was stirred at roomtemperature for 16 hr. The reaction mixture was diluted with ethylacetate, washed with 5% aqueous potassium hydrogensulfate solution andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.21 g, 28%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.05 (t, J=7.2 Hz, 3H), 1.31-1.86 (m,6H), 2.09-2.25 (m, 2H), 2.60-2.81 (m, 2H), 2.97-3.06 (m, 2H), 3.25-3.50(m, 4H), 4.01 (s, 2H), 4.99-5.16 (m, 1H), 7.31-7.53 (m, 6H), 7.57-7.66(m, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.92 (s, 1H)

Reference Example 135N-[4-(prop-2-en-1-yloxy)cyclohexyl]-4H-1,2,4-triazol-3-amine

To a solution (100 mL) of 1H-1,2,4-triazol-3-amine (2.4 g) and4-(prop-2-en-1-yloxy)cyclohexanone (5.3 g) in acetic acid was addedsodium cyanoborohydride (9.1 g), and the mixture was stirred at roomtemperature for 16 hr. Water was added to the reaction mixture, and thesolvent was evaporated under reduced pressure. The obtained residue waspoured into saturated aqueous sodium hydrogen carbonate, and the mixturewas extracted with a mixed solvent of ethyl acetate and isopropylalcohol (3:1). The obtained extract was dried over anhydrous sodiumsulfate, and the solvent was evaporated under reduced pressure. Theobtained reaction mixture was purified by silica gel columnchromatography to give the title compound as a colorless solid (3.2 g,50%).

¹H NMR (300 MHz, DMSO-d₆) δ 1.20-1.98 (m, 8H) 3.16-3.40 (m, 1H)3.42-3.52 (m, 1H) 3.86-3.98 (m, 2H) 5.04-5.16 (m, 1H) 5.18-5.37 (m, 1H)5.72-6.04 (m, 1H) 6.39 (br. s., 1H) 6.99-7.70 (m, 1H) 11.70-12.22 (m,1H)

Reference Example 1364′-({5-oxo-4-[4-(prop-2-en-1-yloxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (4g) and N-[4-(prop-2-en-1-yloxy)cyclohexyl]-4H-1,2,4-triazol-3-amine (1.3g) was stirred at 250° C. for 20 min under microwave irradiation. Theobtained reaction mixture was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.7 g,24%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.01-1.13 (m, 3H) 1.39-1.87 (m, 6H)2.06-2.27 (m, 2H) 2.60-3.12 (m, 4H) 3.37-3.57 (m, 0.5H) 3.63-3.71 (m,0.5H) 3.97-4.07 (m, 4H) 4.96-5.13 (m, 1H) 5.14-5.22 (m, 1H) 5.22-5.47(m, 1H) 5.83-6.10 (m, 1H) 7.33-7.54 (m, 6H) 7.58-7.67 (m, 1H) 7.74 (d,J=7.95 Hz, 1H) 7.91 (s, 0.5H) 7.92 (s, 0.5H)

Reference Example 1374′-({4-[4-(2-hydroxyethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-({5-oxo-4-[4-(prop-2-en-1-yloxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.5 g), osmium oxide (7% immobilized catalyst, 0.5 g), sodium periodate(1.1 g), acetone (5 mL), acetonitrile (5 mL) and water (5 mL) wasstirred at room temperature for 3 hr. The reaction mixture was dilutedwith ethyl acetate and water, and the insoluble material was filteredoff through celite. The obtained organic layer was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was dissolved inmethanol (5 mL) and tetrahydrofuran (5 mL), sodium borohydride (0.045 g)was added, and the mixture was stirred at room temperature for 1 hr.After evaporation of the solvent under reduced pressure, the residue wasextracted with water and ethyl acetate. The obtained ethyl acetate layerwas washed with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.4 g, 79%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.01-1.10 (m, 3H), 1.38-1.56 (m, 3H),1.67-1.84 (m, 3H), 2.07-2.25 (m, 2H), 2.62-2.78 (m, 1H), 2.89-3.06 (m,3H), 3.41-3.75 (m, 4H), 3.78-3.85 (m, 1H), 4.02 (d, J=3.0 Hz, 2H),7.33-7.52 (m, 6H), 7.59-7.66 (m, 1H), 7.75 (dd, J=7.7, 1.1 Hz, 1H), 7.92(d, J=6.2 Hz, 1H)

Reference Example 1384′-({4-[4-(2-methoxyethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-({4-[4-(2-hydroxyethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.2 g), sodium hydride (0.019 g) and N,N-dimethylformamide (10 mL) wasstirred at 0° C. for 10 min, methyl iodide (0.029 mL) was added, and themixture was stirred at room temperature for 16 hr. The reaction mixturewas diluted with ethyl acetate, washed with 5% aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.078 g,38%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.01-1.10 (m, 3H), 1.44-1.57 (m, 3H),1.66-1.83 (m, 3H), 2.09-2.25 (m, 2H), 2.64-2.78 (m, 1H), 2.89-3.10 (m,3H), 3.37-3.47 (m, 3H), 3.51-3.67 (m, 5H), 4.02 (d, J=2.6 Hz, 2H),4.96-5.12 (m, 1H), 7.34-7.51 (m, 6H), 7.58-7.66 (m, 1H), 7.71-7.78 (m,1H), 7.91 (d, J=1.9 Hz, 1H)

Reference Example 1392′-fluoro-4′-(hydroxymethyl)biphenyl-2-carbonitrile

A mixture of (2-fluoro-4-formylphenyl)boronic acid (35.3 g),2-cyano-phenylboronic acid (40.0 g),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (1.7 g),tetrabutylammonium bromide (0.68 g), 2M aqueous sodium carbonatesolution (200 mL) and toluene (600 mL) was stirred at 100° C. for 72 hrunder an argon atmosphere. The reaction mixture was diluted with ethylacetate, washed with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure. The obtainedresidue was dissolved in tetrahydrofuran (150 mL) and methanol (150 mL),sodium borohydride (8.7 g) was added, and the mixture was stirred atroom temperature for 1 hr. After evaporation of the solvent underreduced pressure, the residue was extracted with water and ethylacetate. The obtained ethyl acetate layer was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel column chromatography to give the title compound as a colorlesssolid (14.1 g, 30%).

¹H NMR (300 MHz, DMSO-d₆) δ 4.60 (d, J=5.8 Hz, 2H), 5.43 (t, J=5.8 Hz,1H), 7.32 (d, J=3.8 Hz, 2H), 7.46 (t, J=7.9 Hz, 1H), 7.57-7.76 (m, 2H),7.82 (t, J=7.0 Hz, 1H), 7.98 (dd, J=7.7, 0.9 Hz, 1H)

Reference Example 1404′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(20 g), 6N hydrochloric acid (150 mL) and tetrahydrofuran (200 mL) wasstirred at 70° C. for 16 hr. The reaction mixture was diluted with ethylacetate, washed with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (14 g, 77%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.07 (t, J=7.3 Hz, 3H), 1.67-1.80 (m,2H), 2.01-2.13 (m, 2H), 2.51-2.59 (m, 4H), 2.99-3.18 (m, 2H), 4.03 (s,2H), 5.48-5.62 (m, 1H), 7.34-7.53 (m, 6H), 7.58-7.68 (m, 1H), 7.75 (dd,J=7.7, 0.9 Hz, 1H), 7.91 (s, 1H)

Reference Example 1414′-{[4-(4-morpholin-4-ylcyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

To a solution (5 mL) of4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.5 g) and morpholine (0.14 mL) in acetic acid was added sodiumcyanoborohydride (0.34 g), and the mixture was stirred at roomtemperature for 16 hr. Water was added to the reaction mixture, and thesolvent was evaporated under reduced pressure. The obtained residue waspoured into saturated aqueous sodium hydrogen carbonate, and the mixturewas extracted with ethyl acetate. The obtained extract was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.2 g, 35%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.05 (t, J=7.5 Hz, 3H), 1.41-1.77 (m,6H), 2.08-2.26 (m, 3H), 2.50 (br. s., 4H), 2.86-3.05 (m, 4H), 3.75-3.82(m, 4H), 4.03 (s, 2H), 4.98-5.18 (m, 1H), 7.32-7.52 (m, 6H), 7.58-7.67(m, 1H), 7.71-7.76 (m, 1H), 7.92 (s, 1H)

Reference Example 1424′-({5-oxo-4-[4-(2-oxopropoxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-({5-oxo-4-[4-(prop-2-en-1-yloxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(1.8 g), osmium oxide (7% immobilized catalyst, 0.92 g), sodiumperiodate (3.9 g), acetone (20 mL), acetonitrile (20 mL) and water (20mL) was stirred at room temperature for 3 hr. The reaction mixture wasdiluted with ethyl acetate and water, and the insoluble material wasfiltered off through celite. The obtained organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The residue obtained by silicagel chromatography was dissolved in tetrahydrofuran (20 mL), andmethylmagnesium bromide (1.0 M tetrahydrofuran solution, 1.9 mL) wasadded at −78° C. The reaction mixture was warmed to 0° C., and stirredfor 16 hr. Saturated aqueous ammonium chloride solution was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theobtained ethyl acetate layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The residue obtained by silica gel chromatography wasdissolved in acetonitrile (15 mL),1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-on (0.3 g) was added,and the mixture was stirred at room temperature for 3 hr. Saturatedaqueous sodium hydrogen carbonate solution and sodium thiosulfate wereadded to the reaction mixture, and the mixture was stirred at roomtemperature for 2 hr, and extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The obtained residue was purified by silica gel column chromatography togive the title compound as a colorless solid (0.17 g, 68%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.07 (t, J=7.6 Hz, 3H) 1.49-1.80 (m,6H) 2.08-2.18 (m, 2H) 2.33 (s, 3H) 2.91-3.11 (m, 4H) 3.65 (br. s., 1H)4.03 (s, 4H) 4.99-5.15 (m, 1H) 7.34-7.53 (m, 6H) 7.58-7.66 (m, 1H) 7.75(d, J=8.0 Hz, 1H) 7.91 (s, 1H)

Reference Example 1434′-({4-[4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

4′-({5-oxo-4-[4-(2-oxopropoxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.17 g) was dissolved in tetrahydrofuran (15 mL), and methylmagnesiumbromide (1.0 M tetrahydrofuran solution, 0.27 mL) was added at roomtemperature. The reaction mixture was stirred for 3 hr, saturatedaqueous ammonium chloride solution was added, and the mixture wasextracted with ethyl acetate. The obtained ethyl acetate layer waswashed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The obtained residuewas purified by silica gel column chromatography to give the titlecompound as a colorless solid (0.14 g, 78%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.05 (t, J=7.3 Hz, 3H), 1.30 (s, 6H),1.45-1.78 (m, 6H), 2.08-2.16 (m, 2H), 2.90-3.08 (m, 4H), 3.28 (s, 2H),3.67 (br. s., 2H), 4.02 (s, 2H), 5.10-5.28 (m, 1H), 7.34-7.52 (m, 6H),7.58-7.66 (m, 1H), 7.70-7.79 (m, 1H), 7.92 (s, 1H)

Reference Example 144 4′-(bromomethyl)-2′-fluorobiphenyl-2-carbonitrile

To a solution (150 mL) of2′-fluoro-4′-(hydroxymethyl)biphenyl-2-carbonitrile (14.1 g) in toluenewas added phosphorus tribromide (18.7 g) at room temperature, and themixture was stirred for 16 hr. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and the solvent wasevaporated under reduced pressure, and the residue was extracted withethyl acetate, and the obtained ethyl acetate layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography to give the title compound as acolorless solid (15.3 g, 100%).

¹H NMR (300 MHz, DMSO-d₆) δ 4.79 (s, 2H), 7.43-7.56 (m, 3H), 7.61-7.69(m, 2H), 7.83 (t, J=8.5 Hz, 1H), 7.99 (d, J=7.6 Hz, 1H)

Reference Example 1454′-({4-[cis-4-(2-hydroxyethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-({5-oxo-4-[4-(prop-2-en-1-yloxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(1.1 g), osmium oxide (7% immobilized catalyst, 0.48 g), sodiumperiodate (2.4 g), acetone (15 mL), acetonitrile (15 mL) and water (15mL) was stirred at room temperature for 3 hr. The reaction mixture wasdiluted with ethyl acetate and water, and the insoluble material wasfiltered off through celite. The obtained organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was dissolved inmethanol (20 mL), sodium borohydride (0.13 g) was added, and the mixturewas stirred at room temperature for 1 hr. After evaporation of thesolvent under reduced pressure, the residue was extracted with water andethyl acetate. The obtained ethyl acetate layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.29 g, 26%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.2 Hz, 3H) 1.46-1.63 (m,4H) 1.67-1.77 (m, 2H) 2.08-2.18 (m, 2H) 2.89-3.06 (m, 4H) 3.54-3.62 (m,2H) 3.69-3.88 (m, 4H) 4.02 (s, 2H) 5.13-5.29 (m, 1H) 7.32-7.52 (m, 6H)7.59-7.66 (m, 1H) 7.75 (dd, J=7.6, 1.0 Hz, 1H) 7.93 (s, 1H)

Reference Example 1464′-({4-[trans-4-(2-hydroxyethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-({5-oxo-4-[4-(prop-2-en-1-yloxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(1.1 g), osmium oxide (7% immobilized catalyst, 0.48 g), sodiumperiodate (2.4 g), acetone (15 mL), acetonitrile (15 mL) and water (15mL) was stirred at room temperature for 3 hr. The reaction mixture wasdiluted with ethyl acetate and water, and insoluble material wasfiltered off through celite. The obtained organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The residue was dissolved inmethanol (20 mL), sodium borohydride (0.13 g) was added, and the mixturewas stirred at room temperature for 1 hr. After evaporation of thesolvent under reduced pressure, the residue was extracted with water andethyl acetate. The obtained ethyl acetate layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.23 g, 20%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.3 Hz, 3H), 1.36-1.52 (m,2H), 1.67-1.86 (m, 4H), 1.98-2.04 (m, 1H), 2.13-2.24 (m, 2H), 2.71 (dd,J=12.6, 3.4 Hz, 2H), 2.98-3.07 (m, 2H), 3.38-3.52 (m, 1H), 3.57-3.63 (m,2H), 3.68-3.76 (m, 2H), 4.01 (s, 2H), 5.01-5.15 (m, 1H), 7.33-7.52 (m,6H), 7.59-7.66 (m, 1H), 7.75 (dd, J=7.8, 1.0 Hz, 1H), 7.91 (s, 1H)

Reference Example 1474′-{[4-(4-hydroxy-4-prop-2-en-1-ylcyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.8 g) was dissolved in tetrahydrofuran (10 mL), and allylmagnesiumbromide (1.0 M diethyl ether solution, 2.1 mL) was added at −78° C. Thereaction mixture was warmed to room temperature, and the mixture wasstirred for 16 hr. Saturated aqueous ammonium chloride solution wasadded to the reaction mixture, and the mixture was extracted with ethylacetate. The obtained ethyl acetate layer was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.26 g, 30%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.07 (t, J=7.2 Hz, 3H) 1.62-1.78 (m,6H) 1.82-1.93 (m, 2H) 2.51-2.65 (m, 2H) 2.73-2.91 (m, 1H) 2.97-3.15 (m,2H) 3.39-3.50 (m, 1H) 4.02 (s, 2H) 5.04-5.18 (m, 1H) 5.20-5.30 (m, 2H)5.84-6.02 (m, 1H) 7.32-7.52 (m, 6H) 7.58-7.67 (m, 1H) 7.75 (dd, J=7.7,1.1 Hz, 1H) 7.92 (s, 1H)

Reference Example 1484′-({4-[4-hydroxy-4-(2-hydroxyethyl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-{[4-(4-hydroxy-4-prop-2-en-1-ylcyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.26 g), osmium oxide (7% immobilized catalyst, 0.19 g), sodiumperiodate (0.55 g), acetone (5 mL), acetonitrile (5 mL) and water (5 mL)was stirred at room temperature for 3 hr. The reaction mixture wasdiluted with ethyl acetate and water, and the insoluble material wasfiltered off through celite. The obtained organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The residue was dissolved inmethanol (10 mL), sodium borohydride (0.039 g) was added, and themixture was stirred at room temperature for 1 hr. After evaporation ofthe solvent under reduced pressure, the residue was extracted with waterand ethyl acetate. The obtained ethyl acetate layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.093 g, 36%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.3 Hz, 3H), 1.59-1.77 (m,6H), 1.98-2.16 (m, 4H), 2.62-2.82 (m, 2H), 2.96-3.08 (m, 2H), 3.93-4.05(m, 4H), 5.02-5.17 (m, 1 H), 7.32-7.52 (m, 6H), 7.57-7.67 (m, 1H), 7.75(d, J=7.7 Hz, 1H), 7.91 (s, 1H)

Reference Example 1494′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile

A mixture of ethyl2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (408 g) andN-(1,4-dioxaspiro[4.5]dec-8-yl)-4H-1,2,4-triazol-3-amine (125 g) weredissolved in N,N-diethylaniline (1.5 L) at 160° C. (internaltemperature). A solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (38 mL)in N,N-diethylaniline (400 mL) was added dropwise over 30 min, and themixture was stirred at 180° C. (internal temperature) for 22 hr. Thereaction mixture was cooled to room temperature, and ethyl acetate (1 L)and 3M hydrochloric acid (1 L) were added. The mixture was transferredinto a separatory funnel with ethyl acetate (2 L) and 3M hydrochloridacid (1 L). The organic layer was successively washed with 3Mhydrochloric acid (2 L) twice and brine (2 L), dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The obtainedresidue was purified by silica gel chromatography to give the titlecompound as a brown solid (246 g, 84%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.07 (t, J=7.3 Hz, 3H), 1.66-1.93 (m,8H), 2.90-3.08 (m, 4H), 3.91-4.06 (m, 6H), 5.03-5.20 (m, 1H), 7.21-7.29(m, 2H), 7.34-7.51 (m, 3H), 7.60-7.68 (m, 1H), 7.71-7.80 (m, 1H), 7.96(s, 1H)

Reference Example 1503′-fluoro-4′-{[4-(cis-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile(1 g), 6N hydrochloric acid (10 mL) and tetrahydrofuran (15 mL) wasstirred at 80° C. for 16 hr. The reaction mixture was diluted with ethylacetate, washed with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure. The obtainedresidue was dissolved in methanol (10 mL), sodium borohydride (0.11 g)was added, and the mixture was stirred at room temperature for 1 hr.After evaporation of the solvent under reduced pressure, the residue wasextracted with water and ethyl acetate. The obtained ethyl acetate layerwas washed with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.085 g, 9%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.07 (t, J=7.3 Hz, 3H), 1.54-1.78 (m,6H), 1.92-2.03 (m, 2H), 2.90-3.09 (m, 4H), 4.03 (s, 2H), 4.07-4.14 (m,1H), 5.01-5.20 (m, 1H), 7.22-7.29 (m, 2H), 7.33-7.51 (m, 3H), 7.58-7.69(m, 1H), 7.71-7.80 (m, 1H), 7.95 (s, 1H)

Reference Example 1513′-fluoro-4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile(347 g), 3M hydrochloric acid (1.4 L) and tetrahydrofuran (2.1 L) wasstirred under reflux for 16 hr. The reaction mixture was cooled to roomtemperature, and extracted with ethyl acetate (2 L). The resultingaqueous layer was extracted with ethyl acetate (1 L). The combinedextracts were successively washed with saturated aqueous sodium hydrogencarbonate (1 L) and brine (1 L), dried over anhydrous magnesium sulfate,and concentrated under reduced pressure. The residue obtained wasdissolved in methanol (650 mL) and tetrahydrofuran (960 mL), and theresulting solution was added to a suspension of sodium borohydride (37.3g) in tetrahydrofuran (1.6 L) with the internal temperature maintainedbelow 10° C. After stirring at the same temperature for 0.5 hr,saturated aqueous ammonium chloride solution (640 mL) was added to thereaction mixture, and the solvent was evaporated under reduced pressure.The resulting residue was extracted with ethyl acetate (2 L). Theorganic layer was washed with saturated brine (1 L), dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The resulting residue was purified by silica gel chromatography to givethe title compound as a diastereomeric mixture. The diastereomericmixture obtained was dissolved in ethyl acetate (940 mL) at 50° C.Hexane (1.6 L) was added to the solution, and the resulting mixture wasstirred at the same temperature for 2 hr. Additional hexane (940 mL) wasadded to the mixture, which was cooled to room temperature and stirredfor further 0.5 hr. The precipitate was collected by filtration to givethe title compound as a white solid (233 g, 73%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.07 (t, J=7.3 Hz, 3H), 1.41-1.54 (m,2H), 1.65-1.84 (m, 4H), 2.08-2.17 (m, 2H), 2.64-2.83 (m, 2H), 2.99-3.09(m, 2H), 3.75-3.87 (m, 1H), 4.02 (s, 2H), 4.99-5.12 (m, 1H), 7.20-7.30(m, 2H), 7.33-7.51 (m, 3H), 7.59-7.68 (m, 1H), 7.72-7.79 (m, 1H), 7.92(s, 1H)

Reference Example 152 ethyl4-(4H-1,2,4-triazol-3-ylamino)cyclohexanecarboxylate

To a solution (200 mL) of 1H-1,2,4-triazol-3-amine (11 g) and ethyl4-oxocyclohexanecarboxylate (28 g) in acetic acid was added sodiumcyanoborohydride (35 g), and the mixture was stirred at room temperaturefor 16 hr. Water was added to the reaction mixture, and the solvent wasevaporated under reduced pressure. The obtained residue was poured intosaturated aqueous sodium hydrogen carbonate, and the mixture wasextracted with a mixed solvent of ethyl acetate and isopropyl alcohol(3:1). The obtained extract was dried over anhydrous sodium sulfate, andthe solvent was evaporated under reduced pressure. The obtained residuewas purified by silica gel column chromatography to give the titlecompound as a colorless solid (13 g, 40%).

¹H NMR (300 MHz, DMSO-d₆) δ 1.12-1.69 (m, 8H), 1.81-2.28 (m, 4H),3.13-3.49 (m, 1H), 4.05 (q, J=7.1 Hz, 2H), 5.54, 6.39 (br. s., combined1H), 7.33, 8.01 (br. s, combined 1H), 11.99, 12.72 (br. s., combined 1H)

Reference Example 153 ethyltrans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexanoate

A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (0.5g), ethyl 4-(4H-1,2,4-triazol-3-ylamino)cyclohexanecarboxylate (0.68 g)and N,N-diethylaniline (2.5 mL) was stirred at 180° C. for 16 hr. Theobtained reaction mixture was diluted with ethyl acetate, washed 3 timeswith 1 N hydrochloric acid and saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure andthe residue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.23 g, 31%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.2 Hz, 3H), 1.26 (t, J=7.2Hz, 3H), 1.59-1.90 (m, 6H), 2.09-2.22 (m, 2H), 2.36-2.50 (m, 1H),2.62-2.80 (m, 2H), 2.97-3.05 (m, 2H), 4.02 (s, 2H), 4.06-4.19 (m, 2H),4.98-5.11 (m, 1H), 7.48 (d, J=8.0 Hz, 6H), 7.58-7.67 (m, 1H), 7.74 (d,J=8.0 Hz, 1H), 7.91 (s, 1H)

Reference Example 154trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexanecarboxylicacid

A mixture of ethyltrans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexanoate(13 g), 2 N aqueous sodium hydroxide solution (50 mL), methanol (50 mL)and tetrahydrofuran (50 mL) was stirred at 50° C. for 3 hr. Water (20mL) and 1 N hydrochloric acid were added to the reaction mixture, andthe mixture was adjusted to pH 4, and extracted with ethyl acetate. Theobtained ethyl acetate layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (11 g,93%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.3 Hz, 3H) 1.57-1.78 (m,4H) 1.80-1.91 (m, 2H) 2.15-2.27 (m, 2H) 2.51 (t, J=12.2 Hz, 1H)2.61-2.82 (m, 2H) 2.98-3.07 (m, 2H) 4.02 (s, 2H) 4.99-5.14 (m, 1H)7.33-7.52 (m, 6H) 7.57-7.66 (m, 1H) 7.75 (d, J=7.5 Hz, 1H) 7.89-7.97 (m,1H)

Reference Example 1554′-({4-[trans-4-(3-methyl-1,2,4-oxadiazol-5-yl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture oftrans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexanecarboxylicacid (0.5 g) and thionyl chloride (5 mL) was stirred at 80° C. for 16hr. Toluene (5 mL) was added to the reaction mixture, and the solventwas evaporated under reduced pressure. Toluene (5 mL) was further addedto the obtained residue, and the solvent was evaporated under reducedpressure, and the residue was dissolved in pyridine (5 mL),N′-hydroxyethane imidamide (0.22 g) was added, and the mixture wasstirred at 80° C. for 12 hr. The reaction mixture was diluted with ethylacetate, washed with 1 N hydrochloric acid and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel column chromatography to give the title compound as a colorlesssolid (0.16 g, 29%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.3 Hz, 3H) 1.65-1.89 (m,6H) 1.99 (s, 3H) 2.15-2.27 (m, 2H) 2.52-2.80 (m, 3H) 2.97-3.09 (m, 2H)4.02 (s, 2H) 5.01-5.16 (m, 1H) 7.33-7.51 (m, 6H) 7.58-7.68 (m, 1H)7.71-7.77 (m, 1H) 7.91 (s, 1H)

Reference Example 1564′-{[4-(3,3-dimethyl-1,5-dioxaspiro[5.5]undec-9-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.5 g), 2,2-dimethylpropane-1,3-diol (0.22 g), p-toluenesulfonic acidmonohydrate (0.002 g) and toluene (20 mL) was subjected to an azeotropicdehydration reaction by stirring at 110° C. for 3 hr in a reactionvessel equipped with a Dean-stark trap. The reaction mixture wasconcentrated, and the obtained residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.66 g,100%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.98 (s, 6H) 1.06 (t, J=7.3 Hz, 3H)1.46-1.78 (m, 6H) 2.38-2.49 (m, 2H) 2.80-2.96 (m, 2H) 2.97-3.06 (m, 2H)3.54 (s, 2H) 3.58 (s, 2H) 4.02 (s, 2H) 5.04-5.17 (m, 1H) 7.33-7.51 (m,6H) 7.59-7.66 (m, 1H) 7.74 (d, J=7.7 Hz, 1H) 7.92 (s, 1H)

Reference Example 1572-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]ethylmethanesulfonate

A mixture of4′-({4-[trans-4-(2-hydroxyethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(1.2 g), triethylamine (0.38 mL), methanesulfonyl chloride (0.21 mL),N,N-dimethylpyridin-4-amine (0.028 g) and acetonitrile (20 mL) wasstirred at room temperature for 3 hr. The reaction mixture was washedwith water and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The obtained residue was purified by silica gel column chromatography togive the title compound as a colorless solid (1.2 g, 89%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.3 Hz, 3H) 1.37-1.52 (m,2H) 1.65-1.86 (m, 4H) 2.11-2.24 (m, 2H) 2.61-2.82 (m, 2H) 2.97-3.09 (m,5H) 3.37-3.54 (m, 1H) 3.76 (dd, J=5.4, 3.7 Hz, 2H) 4.01 (s, 2H) 4.37(dd, J=5.5, 3.8 Hz, 2H) 5.06 (t, J=12.4 Hz, 1H) 7.32-7.52 (m, 6H)7.58-7.68 (m, 1H) 7.75 (d, J=7.7 Hz, 1H) 7.91 (s, 1H)

Reference Example 1584′-({4-[trans-4-(2-morpholin-4-ylethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]ethylmethanesulfonate (0.3 g), morpholine (0.88 g), sodium iodide (0.015 g)and tetrahydrofuran (10 mL) was stirred at 70° C. for 5 hr. The reactionmixture was concentrated, and the obtained residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.3 g, 100%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.4 Hz, 3H), 1.37-1.53 (m,2H), 1.65-1.85 (m, 4H), 2.12-2.22 (m, 2H), 2.48-2.54 (m, 4H), 2.55-2.77(m, 4H), 2.97-3.07 (m, 2H), 3.34-3.47 (m, 1H), 3.60-3.76 (m, 6H), 4.01(s, 2H), 4.99-5.14 (m, 1H), 7.32-7.53 (m, 6H), 7.59-7.67 (m, 1H), 7.74(d, J=7.6 Hz, 1H), 7.91 (s, 1H)

Reference Example 1594′-[(4-{trans-4-[2-(1H-imidazol-1-yl)ethoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

To a mixture of2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]ethylmethanesulfonate (0.3 g), imidazole (0.042 g) and N,N-dimethylformamide(5 mL) was added sodium hydride (0.024 g), and the mixture was stirredat 60° C. for 2 hr. The reaction mixture was diluted with ethyl acetate,washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.24 g,83%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.3 Hz, 3H), 1.33-1.49 (m,2H), 1.64-1.84 (m, 4H), 2.06-2.16 (m, 2H), 2.59-2.76 (m, 2H), 2.97-3.06(m, 2H), 3.30-3.42 (m, 1H), 3.73 (t, J=5.2 Hz, 2H), 4.01 (s, 2H),4.05-4.11 (m, 2H), 4.97-5.12 (m, 1H), 7.02 (d, J=19.4 Hz, 2H), 7.32-7.56(m, 7H), 7.58-7.66 (m, 1H), 7.75 (dd, J=7.7, 0.9 Hz, 1H), 7.90 (s, 1H)

Reference Example 160trans-N′-acetyl-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexanecarbohydrazide

A mixture oftrans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexanecarboxylicacid (0.5 g), acetohydrazide (0.09 g), 1-hydroxybenzotriazole (0.19 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.23 g) andN,N-dimethylformamide (10 mL) was stirred at room temperature for 16 hr.The reaction mixture was diluted with ethyl acetate, washed with waterand then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.4 g, 72%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.3 Hz, 3H), 1.41-1.95 (m, 11H),2.20-2.34 (m, 1H), 2.52-2.67 (m, 2H), 2.91-3.02 (m, 2H), 4.00 (s, 2H),4.83-4.99 (m, 1H), 7.36-7.44 (m, 2H), 7.45-7.62 (m, 4H), 7.73-7.82 (m,1H), 7.93 (d, J=8.1 Hz, 1H), 8.20 (s, 1H), 9.65-9.74 (m, 2H)

Reference Example 1614′-({4-[trans-4-(5-methyl-1,3,4-oxadiazol-2-yl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture oftrans-N′-acetyl-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexanecarbohydrazide(0.4 g), p-toluenesulfonyl chloride (0.42 g) and pyridine (10 mL) wasstirred at 110° C. for 5 hr. The reaction mixture was diluted with ethylacetate, washed with 1 N hydrochloric acid and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel column chromatography to give the title compound as a colorlesssolid (0.33 g, 85%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.07 (t, J=7.3 Hz, 3H), 1.67-1.97 (m,6H), 2.32 (d, J=15.3 Hz, 2H), 2.51 (s, 3H), 2.73-2.92 (m, 2H), 2.96-3.08(m, 3H), 4.02 (s, 2H), 5.05-5.24 (m, 1H), 7.33-7.52 (m, 6H), 7.58-7.66(m, 1H), 7.75 (d, J=7.7 Hz, 1H), 7.92 (s, 1H)

Reference Example 1624′-({4-[trans-4-(hydroxymethyl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a mixture oftrans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexanecarboxylicacid (7 g), N-methylmorpholine (1.9 mL) and tetrahydrofuran (100 mL) wasadded ethyl chlorocarbonate (1.6 mL) at 0° C., and the mixture wasstirred at the same temperature for 2 hr. The reaction mixture wascooled to −15° C., sodium borohydride (1.6 g) and methanol (25 mL) wereadded, and the mixture was allowed to gradually warm to roomtemperature. Saturated aqueous ammonium chloride solution was added tothe reaction mixture, and the mixture was extracted with ethyl acetate.The ethyl acetate layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (5.3 g,78%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.3 Hz, 3H), 1.11-1.26 (m,2H), 1.34 (br. s., 1H), 1.64-1.87 (m, 5H), 1.92-2.02 (m, 2H), 2.60-2.75(m, 2H), 2.98-3.07 (m, 2H), 3.51 (d, J=6.4 Hz, 2H), 4.02 (s, 2H),4.96-5.09 (m, 1H), 7.33-7.51 (m, 6H), 7.59-7.67 (m, 1H), 7.75 (d, J=7.7Hz, 1H), 7.92 (s, 1H)

Reference Example 1634′-{[4-(trans-4-formylcyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

To a mixture of4′-({4-[trans-4-(hydroxymethyl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(5.3 g), triethylamine (7.7 mL) and dimethyl sulfoxide (25 mL) was addeda solution (40 mL) of sulfur trioxide-pyridine complex (5.3 g) indimethyl sulfoxide at room temperature, and the mixture was stirred for2 hr. The reaction mixture was poured into 1 N hydrochloric acid, andthe mixture was extracted with ethyl acetate. The obtained ethyl acetatelayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The obtained residue was purified by silica gel column chromatography togive the title compound as a colorless solid (5 g, 95%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.4 Hz, 3H), 1.40-1.54 (m,2H), 1.66-1.81 (m, 2H), 1.84-1.94 (m, 2H), 2.13-2.26 (m, 2H), 2.33-2.47(m, 1H), 2.61-2.83 (m, 2H), 2.98-3.08 (m, 2H), 4.02 (s, 2H), 4.95-5.11(m, 1H), 7.33-7.51 (m, 6H), 7.58-7.67 (m, 1H), 7.75 (d, J=7.2 Hz, 1H),7.91 (s, 1H), 9.67 (s, 1H)

Reference Example 1644′-[(4-{trans-4-[hydroxy(4-methoxyphenyl)methyl]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

4′-{[4-(trans-4-Formylcyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(2.6 g) was dissolved in tetrahydrofuran (50 mL), andbromo(4-methoxyphenyl)magnesium (0.5M tetrahydrofuran solution, 16 mL)was added at −78° C. The reaction mixture was stirred at −78° C. for 2hr, 1 N hydrochloric acid was added, and the mixture was extracted withethyl acetate. The obtained ethyl acetate layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography to give the title compound as acolorless solid (2.2 g, 70%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.05 (t, J=7.4 Hz, 3H), 1.47-1.89 (m,8H), 2.18-2.30 (m, 1H), 2.47-2.78 (m, 3H), 2.96-3.05 (m, 2H), 3.81 (s,3H), 4.00 (s, 2H), 4.34 (d, J=7.3 Hz, 1H), 4.92-5.08 (m, 1H), 6.84-6.92(m, 2H), 7.21-7.27 (m, 2H), 7.31-7.51 (m, 6H), 7.58-7.67 (m, 1 H),7.70-7.76 (m, 1H), 7.88-7.92 (m, 1H)

Reference Example 1654′-[(4-{trans-4-[(4-methoxyphenyl)carbonyl]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

To a mixture of4′-[(4-{trans-4-[hydroxy(4-methoxyphenyl)methyl]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(2.2 g), triethylamine (2.6 mL) and dimethyl sulfoxide (10 mL) was addeda solution (10 mL) of sulfur trioxide-pyridine complex (1.8 g) indimethyl sulfoxide at room temperature, and the mixture was stirred for2 hr. The reaction mixture was poured into 1 N hydrochloric acid, andthe mixture was extracted with ethyl acetate. The obtained ethyl acetatelayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The obtained residue was purified by silica gel column chromatography togive the title compound as a colorless solid (1.7 g, 77%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.07 (t, J=7.3 Hz, 3H), 1.67-1.95 (m,6H), 2.01-2.12 (m, 2H), 2.72-2.91 (m, 2H), 2.97-3.10 (m, 2H), 3.33-3.47(m, 1H), 3.88 (s, 3H), 4.03 (s, 2H), 5.05-5.20 (m, 1H), 6.95 (d, J=8.9Hz, 2H), 7.35-7.53 (m, 6H), 7.58-7.68 (m, 1H), 7.74 (d, J=7.7 Hz, 1H),7.92-8.02 (m, 3H)

Reference Example 166trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexanecarboxamide

A mixture oftrans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexanecarboxylicacid (0.5 g), 1-hydroxybenzotriazole ammonium salt (0.21 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.23 g) andN,N-dimethylformamide (10 mL) was stirred at room temperature for 16 hr.The reaction mixture was diluted with ethyl acetate, washed with waterand then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.36 g, 67%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.3 Hz, 3H) 1.37-1.64 (m, 4H)1.67-1.77 (m, 2H) 1.82-1.94 (m, 2H) 2.10-2.24 (m, 1H) 2.51-2.63 (m, 2H)2.92-3.01 (m, 2H) 4.00 (s, 2H) 4.82-4.98 (m, 1H) 6.74 (br. s., 1H) 7.25(br. s., 1H) 7.37-7.43 (m, 2H) 7.46-7.52 (m, 2H) 7.53-7.63 (m, 2H)7.72-7.81 (m, 1H) 7.93 (d, J=7.7 Hz, 1H) 8.19 (s, 1H)

Reference Example 1674′-{[4-(2,2-dimethyl-1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.5 g), 2-methylpropane-1,2-diol (0.15 g), p-toluenesulfonic acidmonohydrate (0.02 g) and toluene (15 mL) was subjected to an azeotropicdehydration reaction by stirring at 110° C. for 16 hr in a reactionvessel equipped with a Dean-stark trap. The reaction mixture wasconcentrated under reduced pressure, and the obtained residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.66 g, 100%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.4 Hz, 3H), 1.33 (d, J=7.7Hz, 6H), 1.66-1.83 (m, 6H), 1.86-1.98 (m, 2H), 2.87-3.08 (m, 4H),3.71-3.82 (m, 2H), 4.02 (s, 2H), 4.98-5.22 (m, 1H), 7.34-7.51 (m, 6H),7.58-7.66 (m, 1 H), 7.74 (d, J=7.7 Hz, 1H), 7.95 (s, 1H)

Reference Example 1684′-{[4-(trans-4-{2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]ethoxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]ethylmethanesulfonate (0.3 g), cis-2,6-dimethylmorpholine (1.2 g), sodiumiodide (0.015 g) and tetrahydrofuran (10 mL) was stirred at 70° C. for 5hr. The reaction mixture was concentrated, and the obtained residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.3 g, 96%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.3 Hz, 3H), 1.14 (d, J=6.2Hz, 6H), 1.35-1.52 (m, 2H), 1.67-1.85 (m, 6H), 2.11-2.22 (m, 2H), 2.56(t, J=6.0 Hz, 2H), 2.61-2.81 (m, 4H), 2.98-3.06 (m, 2H), 3.35-3.47 (m,1H), 3.59-3.75 (m, 4H), 4.01 (s, 2H), 5.00-5.13 (m, 1H), 7.33-7.51 (m,6H), 7.58-7.66 (m, 1H), 7.74 (d, J=7.7 Hz, 1H), 7.91 (s, 1H)

Reference Example 1694′-{[5-oxo-7-propyl-4-(2,2,3,3-tetramethyl-1,4-dioxaspiro[4.5]dec-8-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.5 g), 2,3-dimethylbutane-2,3-diol (0.57 g), p-toluenesulfonic acidmonohydrate (0.061 g) and toluene (30 mL) was subjected to an azeotropicdehydration reaction by stirring at 110° C. for 16 hr in a reactionvessel equipped with a Dean-stark trap. The reaction mixture wasconcentrated under reduced pressure, and the obtained residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.85 g, 47%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.3 Hz, 3H), 1.24 (s, 6H),1.27 (s, 6H), 1.65-1.83 (m, 6H), 1.91-2.00 (m, 2H), 2.86-3.06 (m, 4H),4.02 (s, 2H), 4.97-5.10 (m, 1H), 7.33-7.52 (m, 6H), 7.58-7.66 (m, 1H),7.74 (d, J=7.7 Hz, 1H), 7.95 (s, 1H)

Reference Example 1704′-({4-[cis-4-(2-hydroxyethoxy)-4-methylcyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution (15 mL) of4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(1 g) in methylene chloride was added trimethylaluminum (1.4M hexanesolution, 11 mL) at 0° C., and the mixture was stirred at 40° C. for 40hr. Methanol (1 mL) was gradually added to the reaction mixture, themixture was poured into 1 N hydrochloric acid, and the mixture wasextracted with ethyl acetate. The obtained ethyl acetate layer waswashed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.36 g, 35%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.2 Hz, 3H), 1.20 (s, 3H),1.37-1.56 (m, 4H), 1.67-1.78 (m, 2H), 1.94-2.03 (m, 2H), 2.91-3.06 (m,4H), 3.46-3.51 (m, 2H), 3.78-3.85 (m, 2H), 4.02 (s, 2H), 4.43 (br. s.,1H), 5.13-5.26 (m, 1H), 7.34-7.51 (m, 6H), 7.59-7.66 (m, 1H), 7.75 (d,J=8.0 Hz, 1H), 7.94 (s, 1H)

Reference Example 1714′-({4-[trans-4-(2-hydroxyethoxy)-4-methylcyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution (15 mL) of4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(1 g) in methylene chloride was added trimethylaluminum (1.4M hexanesolution, 11 mL) at 0° C., and the mixture was stirred at 40° C. for 40hr. Methanol (1 mL) was gradually added to the reaction mixture, themixture was poured into 1 N hydrochloric acid, and the mixture wasextracted with ethyl acetate. The obtained ethyl acetate layer waswashed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.44 g, 43%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.4 Hz, 3H), 1.44 (s, 3H),1.64-1.77 (m, 6H), 1.83-1.93 (m, 2H), 2.06-2.13 (m, 1H), 2.71-2.89 (m,2H), 2.95-3.06 (m, 2H), 3.50-3.58 (m, 2H), 3.66-3.73 (m, 2H), 4.02 (s,2H), 4.99-5.16 (m, 1H), 7.33-7.51 (m, 6H), 7.58-7.67 (m, 1H), 7.74 (d,J=8.0 Hz, 1H), 7.92 (s, 1H)

Reference Example 172 ethyl5-(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)-1,3-oxazole-4-carboxylate

To a mixture oftrans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexanecarboxylicacid (1.2 g), oxalyl chloride (0.25 mL) and tetrahydrofuran (15 mL) wasadded N,N-dimethylformamide (1 drop), and the mixture was stirred atroom temperature for 3 hr. The reaction mixture was concentrated, theobtained residue was dissolved in tetrahydrofuran (5 mL), and thesolution was added to potassium tert-butoxide (0.54 g), ethylisocyanoacetate (0.54 g) and tetrahydrofuran (5 mL) stirred at 0° C. for30 min in advance at 0° C. The reaction mixture was stirred at 0° C. for1 hr, and the mixture was extracted with 1 N hydrochloric acid and ethylacetate. The obtained ethyl acetate layer was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (1.3 g, 91%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.07 (t, J=7.4 Hz, 3H), 1.42 (t, J=7.2Hz, 3H), 1.70-1.93 (m, 6H), 2.05-2.15 (m, 2H), 2.78-2.95 (m, 2H),3.00-3.08 (m, 2H), 3.61-3.73 (m, 1H), 4.03 (s, 2H), 4.41 (q, J=7.2 Hz,2H), 5.09-5.21 (m, 1H), 7.34-7.52 (m, 6H), 7.58-7.67 (m, 1H), 7.72-7.78(m, 2H), 7.92 (s, 1H)

Reference Example 1735-(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)-1,3-oxazole-4-carboxylicacid

A mixture of ethyl5-(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)-1,3-oxazole-4-carboxylate(1.3 g), 1N aqueous sodium hydroxide solution (10 mL), tetrahydrofuran(10 mL) and methanol (10 mL) was stirred at 50° C. for 16 hr. 1N Aqueoushydrochloric acid solution was added to the reaction mixture, and themixture was extracted with ethyl acetate. The obtained ethyl acetatelayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure togive the title compound as a colorless solid (0.94 g, 76%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.96 (t, J=7.3 Hz, 3H), 1.53-1.88 (m, 6H),1.94-2.05 (m, 2H), 2.60-2.78 (m, 2H), 2.92-3.05 (m, 2H), 3.51 (t, J=12.3Hz, 1H), 4.02 (s, 2H), 4.97-5.12 (m, 1H), 7.40-7.45 (m, 2H), 7.46-7.62(m, 4H), 7.73-7.82 (m, 1H), 7.93 (d, J=7.7 Hz, 1H), 8.22 (s, 1H), 8.34(s, 1H), 13.05 (br. s., 1H)

Reference Example 1744′-({4-[trans-4-(1,3-oxazol-5-yl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of5-(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)-1,3-oxazole-4-carboxylicacid (0.94 g), copper(II) oxide (0.005 g) and quinoline (5 mL) wasstirred at 180° C. for 16 hr. 1 N Hydrochloric acid and ethyl acetatewere added to the reaction mixture, and the insoluble material wasfiltered off through celite. The obtained organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure to give the title compound as acolorless solid (0.65 g, 75%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.07 (t, J=7.3 Hz, 3H), 1.53-1.93 (m,6H), 2.18-2.28 (m, 2H), 2.72-2.90 (m, 3H), 2.97-3.09 (m, 2H), 4.03 (s,2H), 5.05-5.20 (m, 1H), 6.77 (s, 1H), 7.33-7.52 (m, 6H), 7.59-7.68 (m,1H), 7.72-7.79 (m, 2H), 7.92 (s, 1H)

Reference Example 1754′-{[4-(1,5-dioxaspiro[5.5]undec-9-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.5 g), propane-1,3-diol (0.12 g), p-toluenesulfonic acid monohydrate(0.01 g) and toluene (15 mL) was subjected to an azeotropic dehydrationreaction by stirring at 110° C. for 16 hr in a reaction vessel equippedwith a Dean-stark trap. The reaction mixture was concentrated, and theobtained residue was purified by silica gel column chromatography togive the title compound as a colorless solid (0.56 g, 100%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.07 (t, J=7.4 Hz, 3H), 1.44-1.79 (m,8H), 2.40-2.50 (m, 2H), 2.79-2.95 (m, 2H), 2.97-3.06 (m, 2H), 3.91-4.03(m, 6H), 5.02-5.17 (m, 1H), 7.33-7.52 (m, 6H), 7.58-7.66 (m, 1H), 7.75(dd, J=7.6, 0.8 Hz, 1H), 7.92 (s, 1H)

Reference Example 1764′-({4-[trans-4-(3-hydroxypropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-{[4-(1,5-dioxaspiro[5.5]undec-9-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.56 g), sodium cyanoborohydride (0.2 g), boron trifluoride-diethylether complex (0.4 mL) and tetrahydrofuran (15 mL) was stirred at 50° C.for 6 hr. The reaction mixture was diluted with ethyl acetate, washedwith water and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure andthe residue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.28 g, 33%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.4 Hz, 3H), 1.35-1.51 (m,2H), 1.66-1.88 (m, 6H), 2.14-2.24 (m, 2H), 2.41-2.48 (m, 1H), 2.63-2.78(m, 2H), 2.98-3.07 (m, 2H), 3.36-3.51 (m, 1H), 3.70 (t, J=5.7 Hz, 2H),3.74-3.83 (m, 2H), 4.01 (s, 2H), 5.00-5.13 (m, 1H), 7.32-7.52 (m, 6H),7.59-7.67 (m, 1H), 7.75 (dd, J=7.7, 1.1 Hz, 1H), 7.91 (s, 1H)

Reference Example 177 ethyltrans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}-1-methylcyclohexanecarboxylate

To a solution (20 mL) of ethyltrans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexanoate(1.9 g) in tetrahydrofuran was added potassium hexamethyldisilazide (1.1M tetrahydrofuran solution, 3.9 mL) at −78° C., and the mixture wasstirred at the same temperature for 1 hr. Methyl iodide (0.33 mL) wasadded to the reaction mixture, and the mixture was warmed to roomtemperature and stirred for 16 hr. The reaction mixture was poured into1 N hydrochloric acid, and the mixture was extracted with ethyl acetate.The obtained ethyl acetate layer was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The obtained residue was dissolved in tetrahydrofuran(20 mL), potassium hexamethyldisilazide (1.1 M tetrahydrofuran solution,3.9 mL) was added at −78° C., and the mixture was stirred at the sametemperature for 1 hr. Methyl iodide (0.33 mL) was added to the reactionmixture, and the mixture was warmed to room temperature and stirred for16 hr. The reaction mixture was poured into 1 N hydrochloric acid, andthe mixture was extracted with ethyl acetate. The obtained ethyl acetatelayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure andthe residue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.58 g, 30%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.05 (t, J=7.4 Hz, 3H) 1.20 (s, 3H)1.34 (t, J=7.1 Hz, 3H) 1.57-1.76 (m, 6H) 2.30-2.41 (m, 2H) 2.66-2.84 (m,2H) 2.96-3.04 (m, 2H) 4.01 (s, 2H) 4.28 (q, J=7.0 Hz, 2H) 4.97-5.11 (m,1H) 7.33-7.51 (m, 6H) 7.59-7.66 (m, 1H) 7.75 (dd, J=7.7, 0.9 Hz, 1H)7.85 (s, 1H)

Reference Example 1784′-({4-[trans-4-(hydroxymethyl)-4-methylcyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution (15 mL) of ethyltrans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}-1-methylcyclohexanecarboxylate(0.56 g) in tetrahydrofuran was added diisobutylaluminum hydride (1.0 Mhexane solution, 10 mL) at −78° C., and the mixture was stirred at thesame temperature for 6 hr. The reaction mixture was poured into 1 Nhydrochloric acid, and the mixture was extracted with ethyl acetate. Theobtained ethyl acetate layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.22 g,43%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.98 (s, 3H), 1.06 (t, J=7.3 Hz, 3H),1.29-1.42 (m, 2H), 1.50-1.83 (m, 6H), 2.66-2.85 (m, 2H), 2.97-3.06 (m,2H), 3.78 (s, 2H), 3.99-4.05 (m, 2H), 4.96-5.11 (m, 1H), 7.34-7.52 (m,6H), 7.58-7.67 (m, 1H), 7.71-7.78 (m, 1H), 7.91 (s, 1H)

Reference Example 1794′-({4-[(3R,6R)-1-oxaspiro[2.5]oct-6-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a mixture of trimethylsulfoxonium iodide (0.57 g) and dimethylsulfoxide (10 mL) was added sodium hydride, and the mixture was stirredat room temperature for 30 min. A solution of4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(1 g) in dimethyl sulfoxide (5 mL) was added to the reaction mixture,and the mixture was further stirred at room temperature for 3 hr. Thereaction mixture was extracted with water and ethyl acetate. Theobtained ethyl acetate layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.72 g,70%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.07 (t, J=7.4 Hz, 3H) 1.37-1.46 (m,2H) 1.67-1.84 (m, 4H) 2.07-2.19 (m, 2H) 2.71 (s, 2H) 2.97-3.14 (m, 4H)4.03 (s, 2H) 5.11-5.26 (m, 1H) 7.33-7.51 (m, 6H) 7.58-7.68 (m, 1H) 7.74(d, J=7.9 Hz, 1H) 7.93 (s, 1H)

Reference Example 1804′-({4-[cis-4-hydroxy-4-(morpholin-4-ylmethyl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-({4-[(3R,6R)-1-oxaspiro[2.5]oct-6-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.72 g), morpholine (3.9 g) and tetrahydrofuran (10 mL) was stirred at70° C. for 48 hr. The reaction mixture was concentrated and the obtainedresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.56 g, 65%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.3 Hz, 3H), 1.39-1.83 (m,8H), 2.35 (s, 2H), 2.59-2.68 (m, 4H), 2.98-3.28 (m, 4H), 3.67-3.75 (m,4H), 4.02 (s, 2H), 4.98-5.15 (m, 1H), 7.33-7.51 (m, 6H), 7.58-7.67 (m,1H), 7.70-7.78 (m, 1H), 7.95 (s, 1H)

Reference Example 181 ethyl(4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexylidene)acetate

To a solution (10 mL) of ethyl (diethoxyphosphoryl)acetate (1.2 g) intetrahydrofuran was added sodium hydride (0.21 g), and the mixture wasstirred at room temperature for 1 hr. A solution (10 mL) of4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(2 g) in tetrahydrofuran was added to the reaction mixture, and themixture was stirred at room temperature for 3 hr. The reaction mixturewas extracted with 1 N hydrochloric acid and ethyl acetate, and theobtained ethyl acetate layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (1.9 g,86%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.4 Hz, 3H), 1.28 (t, J=7.2Hz, 3H), 1.66-1.80 (m, 2H), 1.87-1.98 (m, 2H), 1.99-2.12 (m, 2H),2.33-2.51 (m, 2H), 2.65-2.89 (m, 2H), 2.98-3.08 (m, 2H), 4.02 (s, 2H),4.07-4.19 (m, 2H), 5.23-5.38 (m, 1H), 5.71 (s, 1H), 7.35-7.52 (m, 6H),7.58-7.67 (m, 1H), 7.75 (d, J=7.6 Hz, 1H), 7.90 (s, 1H)

Reference Example 1824′-({4-[4-(2-hydroxyethylidene)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of calcium chloride (1.6 g), sodium borohydride (1.1 g),tetrahydrofuran (40 mL) and ethanol (40 mL) was stirred at 0° C. for 1hr. A solution (20 mL) of ethyl(4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexylidene)acetate(1.9 g) in tetrahydrofuran was added to the reaction mixture, and themixture was stirred at room temperature for 16 hr. The reaction mixturewas extracted with 1 N hydrochloric acid and ethyl acetate, and theobtained ethyl acetate layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.9 g,49%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.4 Hz, 3H), 1.64-1.79 (m,2H), 1.82-2.00 (m, 3H), 2.22-2.44 (m, 2H), 2.59-2.86 (m, 3H), 2.99-3.07(m, 2H), 3.73 (br. s., 1H), 4.02 (s, 2H), 4.14-4.22 (m, 2H), 5.18-5.30(m, 1H), 5.45-5.53 (m, 1H), 7.34-7.51 (m, 6H), 7.58-7.67 (m, 1H), 7.75(d, J=7.7 Hz, 1H), 7.91 (s, 1H)

Reference Example 1834′-({4-[4-hydroxy-4-(trifluoromethyl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution (10 mL) of 1H-1,2,4-triazol-3-amine (0.39 g) and4-hydroxy-4-(trifluoromethyl)cyclohexanone (1 g) in acetic acid wasadded sodium cyanoborohydride (1.5 g), and the mixture was stirred atroom temperature for 16 hr. Water was added to the reaction mixture, andthe solvent was evaporated under reduced pressure. The obtained residuewas poured into saturated aqueous sodium hydrogen carbonate, and themixture was extracted with a mixed solvent of ethyl acetate andisopropyl alcohol (3:1). The obtained extract was dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure. Amixture of the residue obtained by purification by silica gel columnchromatography and ethyl2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (2.5 g) was stirred at250° C. for 30 min under microwave irradiation. The obtained reactionmixture was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.28 g, 11%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.07 (t, J=7.2 Hz, 3H), 1.68-2.07 (m,8H), 3.04 (dd, 4H), 4.02 (s, 2H), 5.03-5.20 (m, 1H), 7.34-7.52 (m, 6H),7.59-7.68 (m, 1H), 7.75 (d, J=7.7 Hz, 1H), 7.94 (s, 1H)

Reference Example 1844′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (44g), N-(1,4-dioxaspiro[4.5]dec-8-yl)-5-methyl-4H-1,2,4-triazol-3-amine(15 g) and N,N-diethylaniline (100 mL) was stirred at 200° C. for 48 hr.The obtained reaction mixture was diluted with ethyl acetate, washed 3times with 1 N hydrochloric acid and saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (12 g,36%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.04 (t, J=7.3 Hz, 3H), 1.66-1.94 (m,8H), 2.45 (s, 3H), 2.88-3.02 (m, 4H), 3.93-4.06 (m, 6H), 4.98-5.11 (m,1H), 7.32-7.51 (m, 6H), 7.58-7.65 (m, 1H), 7.74 (dd, J=7.7, 0.9 Hz, 1H)

Reference Example 1854′-({4-[trans-4-(2-hydroxyethoxy)-4-methylcyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution (30 mL) of4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(3 g) in methylene chloride was added trimethylaluminum (1.4M hexanesolution, 33 mL) at 0° C., and the mixture was stirred at 40° C. for 72hr. Methanol (3 mL) was gradually added to the reaction mixture, themixture was poured into 1 N hydrochloric acid, and the mixture wasextracted with ethyl acetate. The obtained ethyl acetate layer waswashed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.75 g, 24%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.04 (t, J=7.2 Hz, 3H), 1.45 (s, 3H),1.63-1.76 (m, 6H), 1.81-1.92 (m, 2H), 2.11 (t, J=6.2 Hz, 1H), 2.44 (s,3H), 2.71-2.89 (m, 2H), 2.92-3.01 (m, 2H), 3.51-3.57 (m, 2H), 3.65-3.73(m, 2H), 3.99 (s, 2H), 4.93-5.08 (m, 1H), 7.31-7.51 (m, 6H), 7.57-7.66(m, 1H), 7.74 (d, J=8.0 Hz, 1H)

Reference Example 1864′-({4-[trans-4-(2-hydroxypropoxy)-4-methylcyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a mixture of4′-({4-[trans-4-(2-hydroxyethoxy)-4-methylcyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.75 g), triethylamine (0.97 mL) and dimethyl sulfoxide (5 mL) wasadded a solution (5 mL) of sulfur trioxide-pyridine complex (0.66 g) indimethyl sulfoxide at room temperature, and the mixture was stirred for2 hr. The reaction mixture was poured into 1 N hydrochloric acid, andthe mixture was extracted with ethyl acetate. The obtained ethyl acetatelayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The residue obtained by purification by silica gel column chromatographywas dissolved in tetrahydrofuran (15 mL), methylmagnesium bromide (1.0 Mtetrahydrofuran solution, 4.2 mL) was added at room temperature, and themixture was stirred for 4 hr. 1 N Hydrochloric acid was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theobtained ethyl acetate layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.25 g,33%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.04 (t, J=7.3 Hz, 3H), 1.15 (d, J=6.2Hz, 3H), 1.42 (s, 3H), 1.61-1.76 (m, 6H), 1.79-1.91 (m, 2H), 2.43 (s,3H), 2.51 (br. s., 1H), 2.72-2.89 (m, 2H), 2.92-3.01 (m, 2H), 3.20 (t,J=8.5 Hz, 1H), 3.42 (dd, J=8.9, 3.2 Hz, 1H), 3.83-3.94 (m, 1H), 3.99 (s,2H), 4.92-5.06 (m, 1H), 7.31-7.51 (m, 6H), 7.57-7.67 (m, 1H), 7.74 (d,J=7.7 Hz, 1H)

Reference Example 1874′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)-4-methylcyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a mixture of4′-({4-[trans-4-(2-hydroxypropoxy)-4-methylcyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.25 g), triethylamine (0.63 mL) and dimethyl sulfoxide (5 mL) wasadded a solution (5 mL) of sulfur trioxide-pyridine complex (0.36 g) indimethyl sulfoxide at room temperature, and the mixture was stirred for2 hr. The reaction mixture was poured into 1 N hydrochloric acid, andthe mixture was extracted with ethyl acetate. The obtained ethyl acetatelayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The residue obtained by purification by silica gel column chromatographywas dissolved in tetrahydrofuran (15 mL), methylmagnesium bromide (1.0 Mtetrahydrofuran solution, 1.4 mL) was added at room temperature, and themixture was stirred for 4 hr. 1 N Hydrochloric acid was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theobtained ethyl acetate layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.11 g,43%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.04 (t, J=7.3 Hz, 3H), 1.20 (s, 6H),1.41 (s, 3H), 1.58-1.90 (m, 8H), 2.43 (s, 3H), 2.50 (s, 1H), 2.72-2.89(m, 2H), 2.92-3.01 (m, 2H), 3.24 (s, 2H), 4.00 (s, 2H), 4.93-5.06 (m,1H), 7.32-7.52 (m, 6H), 7.58-7.66 (m, 1H), 7.74 (dd, J=7.7, 0.9 Hz, 1H)

Reference Example 1884′-{[2-methyl-5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(27 g), 6N hydrochloric acid (80 mL) and tetrahydrofuran (160 mL) wasstirred at 70° C. for 16 hr. The reaction mixture was diluted with ethylacetate, washed with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (20 g, 80%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.5 Hz, 3H), 1.66-1.79 (m,2H), 2.04-2.08 (m, 2H), 2.42 (s, 3H), 2.53-2.57 (m, 4H), 2.97-3.18 (m,4H), 4.00 (s, 2H), 5.47-5.54 (m, 1H), 7.34-7.49 (m, 6H), 7.59-7.64 (m,1H), 7.74 (d, J=7.8 Hz, 1H)

Reference Example 1894′-{[4-(4-hydroxycyclohexyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

To a mixture of4′-{[2-methyl-5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(2 g), methanol (15 mL) and tetrahydrofuran (15 mL) was added sodiumborohydride (0.24 g), and the mixture was stirred at room temperaturefor 1 hr. After evaporation of the solvent under reduced pressure, theresidue was extracted with water and ethyl acetate. The obtained ethylacetate layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (1.8 g, 90%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.05 (t, J=7.3 Hz, 3H), 1.42-1.81 (m,6H), 1.92-2.15 (m, 2H), 2.44 (s, 3H), 2.65-2.84 (m, 2H), 2.91-3.03 (m,2H), 3.74-3.88 (m, 1H), 3.99 (s, 2H), 4.90-5.10 (m, 1H), 7.32-7.52 (m,6H), 7.58-7.67 (m, 1H), 7.71-7.77 (m, 1H)

Reference Example 190 ethyl[(4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate

To a mixture of4′-{[4-(4-hydroxycyclohexyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(1.2 g), rhodium(I) acetate (0.055 g) and toluene (40 mL) was addeddropwise ethyl diazoacetate (1.2 mL) at 80° C., and the mixture wasstirred at the same temperature for 1 hr. The reaction mixture wasconcentrated under reduced pressure, and the obtained residue wassubjected to silica gel column chromatography to give the title compoundas a colorless solid (1.1 g, 76%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.03 (t, J=7.4 Hz, 3H), 1.29 (t, J=7.2Hz, 3H), 1.43-1.61 (m, 2H), 1.64-1.83 (m, 4H), 2.11-2.27 (m, 2H), 2.43(s, 3H), 2.63-2.82 (m, 2H), 2.89-3.02 (m, 2H), 3.43-3.74 (m, 1H), 3.99(s, 2H), 4.13 (s, 2H), 4.18-4.28 (m, 2H), 4.90-5.06 (m, 1H), 7.32-7.51(m, 6H), 7.58-7.66 (m, 1H), 7.74 (dd, J=7.7, 0.9 Hz, 1H)

Reference Example 1914′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

Ethyl[(4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate(0.5 g) was dissolved in tetrahydrofuran (10 mL), and methylmagnesiumbromide (1.0 M tetrahydrofuran solution, 4.2 mL) was added at 0° C.After stirring at the same temperature for 1 hr, 1 N hydrochloric acidwas added to the reaction mixture, and the mixture was extracted withethyl acetate. The obtained ethyl acetate layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography to give the title compound as acolorless solid (0.32 g, 56%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.04 (t, J=7.4 Hz, 3H), 1.20 (s, 6H),1.37-1.52 (m, 2H), 1.64-1.84 (m, 4H), 2.12-2.22 (m, 2H), 2.43 (s, 3H),2.62-2.81 (m, 2H), 2.92-3.02 (m, 2H), 3.31 (s, 2H), 3.38-3.51 (m, 1H),3.98 (s, 2H), 4.93-5.07 (m, 1H), 7.30-7.52 (m, 6H), 7.62 (t, J=7.8 Hz,1H), 7.74 (d, J=7.2 Hz, 1H)

Reference Example 1924′-({4-[trans-4-(2-ethyl-2-hydroxybutoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

Ethyl[(4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate(0.6 g) was dissolved in tetrahydrofuran (15 mL), and ethylmagnesiumbromide (3.0 M diethyl ether solution, 1.7 mL) was added at 0° C. Afterstirring at the same temperature for 1 hr, 1 N hydrochloric acid wasadded to the reaction mixture, and the mixture was extracted with ethylacetate. The obtained ethyl acetate layer was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.4 g, 55%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.87 (t, J=7.4 Hz, 6H) 1.04 (t, J=7.4Hz, 3H) 1.35-1.56 (m, 6H) 1.63-1.82 (m, 4H) 2.10-2.21 (m, 2H) 2.43 (s,3H) 2.63-2.79 (m, 2H) 2.92-3.00 (m, 2H) 3.34 (s, 2H) 3.38-3.47 (m, 1H)3.97 (s, 2H) 4.93-5.06 (m, 1H) 7.31-7.52 (m, 6H) 7.62 (t, J=7.8 Hz, 1H)7.74 (d, J=8.0 Hz, 1H)

Reference Example 1934′-{[4-(4-methylidenecyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

To a solution (15 mL) of methyltriphenylphosphonium bromide (1.2 g) intetrahydrofuran was added n-butyllithium (1.6M hexane solution, 2 mL) at0° C., and the mixture was stirred at the same temperature for 30 min.The reaction mixture was warmed to room temperature, and further stirredfor 30 min. A solution (5 mL) of4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(1 g) in tetrahydrofuran was added, and the mixture was stirred at 70°C. for 3 hr. The insoluble material was filtered off, and the obtainedfiltrate was extracted with ethyl acetate and 1 N hydrochloric acid. Theethyl acetate layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.8 g,80%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.3 Hz, 3H), 1.66-1.78 (m,2H), 1.80-1.89 (m, 2H), 2.15-2.31 (m, 2H), 2.40-2.50 (m, 2H), 2.62-2.79(m, 2H), 2.98-3.07 (m, 2H), 4.02 (s, 2H), 4.73 (s, 2H), 5.14-5.28 (m,1H), 7.34-7.52 (m, 6H), 7.58-7.66 (m, 1H), 7.75 (dd, J=7.7, 0.9 Hz, 1H),7.91 (s, 1H)

Reference Example 1944′-({4-[(5S,8S)-3-methyl-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution (15 mL) of4′-{[4-(4-methylidenecyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.8 g) and triethylamine (0.72 mL) in methylene chloride was addedN-hydroxyethanimidoyl chloride (0.49 g) at 0° C. The reaction mixturewas stirred at room temperature for 16 hr, washed with 1 N hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.2 g, 22%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.3 Hz, 3H), 1.60-1.80 (m,6H), 1.98 (s, 3H), 2.05-2.13 (m, 2H), 2.68 (s, 2H), 2.97-3.20 (m, 4H),4.02 (s, 2H), 5.03-5.18 (m, 1H), 7.34-7.51 (m, 6H), 7.58-7.66 (m, 1H),7.75 (dd, J=7.7, 0.9 Hz, 1H), 7.94 (s, 1H)

Reference Example 1954′-({4-[(5R,8R)-3-methyl-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution (15 mL) of4′-{[4-(4-methylidenecyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.8 g) and triethylamine (0.72 mL) in methylene chloride was addedN-hydroxyethanimidoyl chloride (0.49 g) at 0° C. The reaction mixturewas stirred at room temperature for 16 hr, washed with 1 N hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.23 g, 26%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.4 Hz, 3H), 1.64-1.94 (m,8H), 2.01 (s, 3H), 2.65-2.82 (m, 2H), 2.93 (s, 2H), 2.98-3.06 (m, 2H),4.01 (s, 2H), 5.06-5.16 (m, 1H), 7.34-7.51 (m, 6H), 7.59-7.67 (m, 1H),7.75 (dd, J=7.7, 0.9 Hz, 1H), 7.91 (s, 1H)

Reference Example 1964′-{[7-butyl-5-oxo-4-(4-oxocyclohexyl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-{[7-butyl-4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(3.1 g), p-toluenesulfonic acid monohydrate (0.1 g), methanol (50 mL)and tetrahydrofuran (50 mL) was stirred at 60° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The obtained residue was dissolved inacetone (20 mL), 1 N hydrochloric acid (20 mL) was added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (2 g,67%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.96 (t, J=7.2 Hz, 3H), 1.40-1.70 (m,4H), 2.03-2.12 (m, 2H), 2.51-2.60 (m, 4H), 3.01-3.17 (m, 4H), 4.03 (s,2H), 5.48-5.62 (m, 1H), 7.35-7.53 (m, 6H), 7.59-7.67 (m, 1H), 7.75 (dd,J=7.7, 0.9 Hz, 1H), 7.92 (s, 1H)

Reference Example 1974′-{[7-butyl-4-(2,3-dimethyl-1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-{[7-butyl-5-oxo-4-(4-oxocyclohexyl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(1 g), 2,3-dimethylpropane-1,3-diol (0.56 g), p-toluenesulfonic acidmonohydrate (0.036 g) and toluene (30 mL) was subjected to an azeotropicdehydration reaction by stirring at 110° C. for 3 hr in a reactionvessel equipped with a Dean-stark trap. The reaction mixture wasconcentrated under reduced pressure, and the obtained residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (1.2 g, 100%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.95 (t, J=7.3 Hz, 3H) 1.14-1.33 (m,6H) 1.40-1.54 (m, 2H) 1.58-2.01 (m, 8H) 2.84-3.08 (m, 4H) 3.62-3.72 (m,0H) 4.01 (s, 2H) 4.19-4.35 (m, 0H) 5.09 (t, J=12.6 Hz, 1H) 7.35-7.51 (m,6H) 7.59-7.66 (m, 1H) 7.75 (dd, J=7.7, 0.9 Hz, 1H) 7.94-7.96 (m, 1H)

Reference Example 1984′-({7-butyl-4-[trans-4-(2-hydroxy-1-methylpropoxy)cyclohexyl]-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-{[7-butyl-4-(2,3-dimethyl-1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(1.2 g), sodium cyanoborohydride (0.71 g), boron trifluoride-diethylether complex (1.4 mL) and tetrahydrofuran (20 mL) was stirred at 50° C.for 24 hr. The reaction mixture was diluted with ethyl acetate, washedwith water and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.66 g, 53%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.93 (t, J=7.2 Hz, 3H) 1.09-1.22 (m,6H) 1.39-2.37 (m, 9H) 2.63-2.88 (m, 3H) 2.98-3.08 (m, 2H) 3.34-3.68 (m,3H) 4.02 (s, 2H) 5.00-5.16 (m, 1H) 7.29-7.51 (m, 6H) 7.60-7.69 (m, 1H)7.71-7.78 (m, 1H) 7.95 (s, 1H)

Reference Example 1994′-({7-butyl-4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-({7-butyl-4-[trans-4-(2-hydroxy-1-methylpropoxy)cyclohexyl]-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.66 g), 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.76g) and acetonitrile (20 mL) was stirred at room temperature for 3 hr.Saturated aqueous sodium hydrogen carbonate solution and sodiumthiosulfate were added to the reaction mixture, and the mixture wasstirred at room temperature for 2 hr, and extracted with ethyl acetate.The organic layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The obtained residue was dissolved in tetrahydrofuran (15 mL),and methylmagnesium bromide (1.0 M tetrahydrofuran solution, 2.4 mL) wasadded at 0° C. The reaction mixture was warmed to 0° C., and stirred for6 hr. 1 N Hydrochloric acid was added to the reaction mixture, and themixture was extracted with ethyl acetate. The obtained ethyl acetatelayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The obtained residue was purified by silica gel column chromatography togive the title compound as a colorless solid (0.32 g, 47%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.95 (t, J=7.2 Hz, 3H), 1.09-1.14 (m,6H), 1.17 (s, 3H), 1.35-1.55 (m, 4H), 1.60-1.85 (m, 4H), 2.03-2.24 (m,2H), 2.59-2.81 (m, 2H), 3.00-3.08 (m, 2H), 3.34 (q, J=6.1 Hz, 1H),3.43-3.57 (m, 1H), 4.01 (s, 2H), 4.99-5.15 (m, 1H), 7.33-7.51 (m, 6H),7.63 (t, J=7.8 Hz, 1H), 7.75 (d, J=7.2 Hz, 1H), 7.92 (s, 1H)

Reference Example 200N-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-4H-1,2,4-triazol-3-amine

To a solution (30 mL) of 1H-1,2,4-triazol-3-amine (3 g) and4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexanone (10 g) in acetic acidwas added sodium cyanoborohydride (9.3 g), and the mixture was stirredat room temperature for 16 hr. Water was added to the reaction mixture,and the solvent was evaporated under reduced pressure. The obtainedresidue was poured into saturated aqueous sodium hydrogen carbonate, andthe mixture was extracted with a mixed solvent of ethyl acetate andisopropyl alcohol (3:1). The obtained extract was dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure.The obtained residue was purified by silica gel column chromatography togive the title compound as a colorless solid (2.2 g, 20%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.00 (s, 6H) 0.85 (s, 9H) 1.44-1.81 (m,9H) 3.44 (br. s., 1H) 3.80-3.90 (m, 1H) 4.79 (br. s., 1H) 7.57-7.65 (m,1H)

Reference Example 2014′-[(7-butyl-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

A solution of 1H-1,2,4-triazol-3-amine (1.5 g) and methyl2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate (7.1 g) in1,2,4-trichlorobenzene (70 mL) was stirred at 190° C. for 6 hr. Afterevaporation of the solvent under reduced pressure, ethyl acetate wasadded to the obtained residue. The precipitated solid was collected byfiltration to give the title compound as a colorless solid (3.6 g, 44%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (t, J=7.2 Hz, 3H) 1.27-1.57 (m, 4H)2.91-3.03 (m, 2H) 3.96 (s, 2H) 7.37-7.44 (m, 2H) 7.46-7.62 (m, 4H)7.73-7.82 (m, 1H) 7.93 (dd, J=7.7, 0.9 Hz, 1H) 8.12 (s, 1H) 13.13 (br.s., 1H)

Reference Example 2023′-fluoro-4′-({4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(retention time: long)

The racemate (500 g) of the title compound obtained in Reference Example107 was resolved using a chiral column to give the title compound as acolorless solid (185 g, 99% ee, 37%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90-1.11 (m, 12H), 1.16-1.39 (m, 2H),1.54-1.75 (m, 4H), 1.94-2.14 (m, 2H), 2.47-2.68 (m, 2H), 2.91-3.02 (m,2H), 3.24 (q, J=6.0 Hz, 1H), 3.30-3.44 (m, 1H), 3.97 (s, 2H), 4.06 (s,1H), 4.80-4.97 (m, 1H), 7.26-7.39 (m, 2H), 7.41-7.50 (m, 1H), 7.54-7.67(m, 2H), 7.75-7.83 (m, 1H), 7.95 (d, J=7.6 Hz, 1H), 8.20 (s, 1H)

Analysis of Enantiomeric Excess

column: CHIRALPAK IA 4.6 mm ID×250 mL

mobile phase: n-Hex/IPA=90/10 (v/v)

flow rate: 1.0 mL/min

temperature: 40° C.

detection: UV 254 nm

concentration: 1 mg/mL (n-Hex/IPA=90/10)

injection volume: 0.01 mL

retention time: 26.4 min

Reference Example 2034′-({5-oxo-7-propyl-4-[(3a′R,6a′S)-tetrahydrospiro[cyclohexane-1,2′-furo[3,4-d][1,3]dioxol]-4-yl]-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.75 g), tetrahydrofuran-3,4-diol (0.48 g), p-toluenesulfonic acidmonohydrate (0.028 g) and toluene (25 mL) was subjected to an azeotropicdehydration reaction by stirring at 110° C. for 16 hr in a reactionvessel equipped with a Dean-stark trap. The reaction mixture wasconcentrated under reduced pressure, and the obtained residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.77 g, 90%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.3 Hz, 3H), 1.57-2.11 (m,8H), 2.83-3.07 (m, 4H), 3.39-3.47 (m, 2H), 4.00-4.18 (m, 4H), 4.75-4.86(m, 2H), 5.02-5.15 (m, 1 H), 7.34-7.52 (m, 6H), 7.58-7.67 (m, 1H), 7.75(dd, J=7.7, 0.9 Hz, 1H), 7.96 (s, 1H)

Reference Example 2044′-{[4-(trans-4-{[(3R,4S)-4-hydroxytetrahydrofuran-3-yl]oxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-({5-oxo-7-propyl-4-[(3a′R,6a′S)-tetrahydrospiro[cyclohexane-1,2′-furo[3,4-d][1,3]dioxol]-4-yl]-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.77 g), sodium cyanoborohydride (0.45 g), boron trifluoride-diethylether complex (0.88 mL) and tetrahydrofuran (20 mL) was stirred at 70°C. for 16 hr. The reaction mixture was diluted with ethyl acetate,washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.14 g,18%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.19 Hz, 3H) 1.42-1.88 (m,6H) 2.07-2.26 (m, 2H) 2.63-2.87 (m, 3H) 2.98-3.08 (m, 2H) 3.39-4.27 (m,9H) 4.99-5.15 (m, 1H) 7.32-7.52 (m, 6H) 7.59-7.67 (m, 1H) 7.75 (d,J=7.57 Hz, 1H) 7.91 (s, 1H)

Reference Example 2054′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

To a mixture of4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(5 g), methanol (20 mL) and tetrahydrofuran (20 mL) was added sodiumborohydride (0.61 g) at 0° C., and the mixture was stirred at the sametemperature for 1 hr. After evaporation of the solvent under reducedpressure, the residue was extracted with water and ethyl acetate. Theobtained ethyl acetate layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (3 g,58%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.35 Hz, 3H) 1.42-1.85 (m,8H) 2.06-2.18 (m, 2H) 2.65-2.82 (m, 2H) 2.98-3.07 (m, 2H) 3.74-3.90 (m,1H) 4.99-5.14 (m, 1H) 7.33-7.53 (m, 6H) 7.59-7.67 (m, 1H) 7.75 (dd,J=7.72, 0.94 Hz, 1H) 7.90-7.93 (m, 1H)

Reference Example 206 ethyl[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate

To a mixture of4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(1 g), rhodium(I) acetate (0.023 g) and methylene chloride (10 mL) wasadded dropwise ethyl diazoacetate (0.64 mL) at room temperature, and themixture was stirred for 1 hr. The reaction mixture was concentrated, andthe obtained residue was subjected to silica gel column chromatographyto give the title compound as a colorless solid (0.68 g, 59%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.35 Hz, 3H) 1.30 (t, J=7.20Hz, 3H) 1.43-1.87 (m, 6H) 2.16-2.28 (m, 2H) 2.62-2.79 (m, 2H) 2.97-3.08(m, 2H) 3.44-3.58 (m, 1H) 4.01 (s, 2H) 4.13 (s, 2H) 4.23 (q, J=7.20 Hz,2H) 5.01-5.14 (m, 1H) 7.33-7.52 (m, 6H) 7.59-7.66 (m, 1H) 7.75 (dd,J=7.82, 1.04 Hz, 1H) 7.91 (s, 1H)

Reference Example 2074′-({4-[(5R,8R)-3-(1-hydroxy-1-methylethyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution (40 mL) of4′-{[4-(4-methylidenecyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.89 g) and triethylamine (5.4 mL) in methylene chloride was addedethyl chloro(hydroxyimino)ethanoate (5.8 g) at 0° C. The reactionmixture was stirred at room temperature for 16 hr, washed with 1 Nhydrochloric acid and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The residue obtained by purification by silica gel columnchromatography was dissolved in tetrahydrofuran (10 mL), and the mixturewas added to a mixture of methylmagnesium bromide (1.0 M tetrahydrofuransolution, 11 mL), cerium chloride anhydrous (0.92 g) and tetrahydrofuran(15 mL) stirred at 0° C. for 1 hr in advance. The reaction mixture wasstirred at 70° C. for 16 hr, 1 N hydrochloric acid was added, and themixture was extracted with ethyl acetate. The obtained ethyl acetatelayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The obtained residue was purified by silica gel column chromatography togive the title compound as a colorless solid (0.12 g, 19%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.35 Hz, 3H) 1.51 (s, 6H)1.65-1.99 (m, 8H) 2.66-2.84 (m, 2H) 2.97-3.08 (m, 4H) 4.02 (s, 2H)5.04-5.18 (m, 1H) 7.33-7.52 (m, 6H) 7.59-7.67 (m, 1H) 7.75 (dd, J=7.72,0.94 Hz, 1H) 7.93 (s, 1H)

Reference Example 2084′-({4-[(5S,8S)-3-(1-hydroxy-1-methylethyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution (40 mL) of4′-{[4-(4-methylidenecyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.89 g) and triethylamine (5.4 mL) in methylene chloride was addedethyl chloro(hydroxyimino)ethanoate (5.8 g) at 0° C. The reactionmixture was stirred at room temperature for 16 hr, washed with 1 Nhydrochloric acid and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The residue obtained by purification by silica gel columnchromatography was dissolved in tetrahydrofuran (10 mL), and the mixturewas added to a mixture of methylmagnesium bromide (1.0 M tetrahydrofuransolution, 9.3 mL), cerium chloride anhydrous (0.77 g) andtetrahydrofuran (15 mL) stirred at 0° C. for 1 hr in advance. Thereaction mixture was stirred at 70° C. for 16 hr, 1 N hydrochloric acidwas added, and the mixture was extracted with ethyl acetate. Theobtained ethyl acetate layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.1 g,19%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.35 Hz, 3H) 1.48 (s, 6H)1.61-1.79 (m, 6H) 2.06-2.18 (m, 2H) 2.82 (s, 2H) 2.99-3.21 (m, 4H) 4.02(s, 2H) 5.12 (t, J=12.62 Hz, 1H) 7.34-7.52 (m, 6H) 7.59-7.67 (m, 1H)7.75 (dd, J=7.72, 0.94 Hz, 1H) 7.95 (s, 1H)

Reference Example 2094′-[(4-{trans-4-[(3-methyl-4,5-dihydroisoxazol-5-yl)methoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

To a solution (40 mL) of4′-({5-oxo-4-[4-(prop-2-en-1-yloxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(2.7 g) and triethylamine (7.5 mL) in methylene chloride was addedN-hydroxyethanimidoyl chloride (5 g) at 0° C. The reaction mixture wasstirred at room temperature for 16 hr, washed with 1 N hydrochloric acidand then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.86 g, 28%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.38 Hz, 3H) 1.35-1.52 (m,2H) 1.66-1.84 (m, 4H) 1.99 (s, 3H) 2.12-2.21 (m, 2H) 2.60-2.85 (m, 3H)2.93-3.07 (m, 3H) 3.41-3.53 (m, 2H) 3.57-3.67 (m, 1H) 4.01 (s, 2H)4.63-4.76 (m, 1H) 4.98-5.12 (m, 1H) 7.34-7.52 (m, 6H) 7.59-7.66 (m, 1H)7.74 (d, J=7.95 Hz, 1H) 7.91 (s, 1H)

Reference Example 210[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]aceticacid

A mixture of ethyl[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate(1.1 g), 1N aqueous sodium hydroxide solution (10 mL), methanol (10 mL)and tetrahydrofuran (10 mL) was stirred at room temperature for 2 hr.The reaction mixture was adjusted to pH 4 with water (20 mL) and 1 Nhydrochloric acid, and extracted with ethyl acetate. The obtained ethylacetate layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The obtained residue was purified by silica gel column chromatography togive the title compound as a colorless solid (0.9 g, 90%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.3 Hz, 3H) 1.23-1.40 (m, 2H)1.54-1.76 (m, 4H) 2.06-2.18 (m, 2H) 2.53-2.66 (m, 2H) 2.91-3.02 (m, 2H)3.29-3.48 (m, 1H) 4.00 (s, 2 H) 4.06 (s, 2H) 4.85-4.98 (m, 1H) 7.38-7.64(m, 6H) 7.74-7.82 (m, 1H) 7.93 (d, J=7.7 Hz, 1H) 8.18 (s, 1H) 12.37 (br.s., 1H)

Reference Example 2112-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide

A mixture of[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]aceticacid (0.9 g), N-methoxymethanamine hydrochloride (0.25 g),1-hydroxybenzotriazole (0.39 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.49 g),triethylamine (0.36 mL) and N,N-dimethylformamide (10 mL) was stirred atroom temperature for 16 hr. The reaction mixture was diluted with ethylacetate, washed with 1 N hydrochloric acid and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.75 g, 77%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.4 Hz, 3H) 1.44-1.85 (m,6H) 2.20-2.31 (m, 2H) 2.62-2.81 (m, 2H) 2.99-3.07 (m, 2H) 3.20 (s, 3H)3.47-3.62 (m, 1H) 3.70 (s, 3H) 4.01 (s, 2H) 4.32 (s, 2H) 5.00-5.15 (m,1H) 7.33-7.50 (m, 6H) 7.59-7.66 (m, 1H) 7.74 (d, J=8.7 Hz, 1H) 7.90 (s,1H)

Reference Example 2124′-({5-oxo-4-[trans-4-(2-oxopropoxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

2-[(trans-4-{6-[(2′-Cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide(0.75 g) was dissolved in tetrahydrofuran (10 mL), and methylmagnesiumbromide (1.0 M tetrahydrofuran solution, 4 mL) was added at roomtemperature. The reaction mixture was warmed to 70° C. and stirred for 3hr. 1 N Hydrochloric acid was added to the reaction mixture, and themixture was extracted with ethyl acetate. The obtained ethyl acetatelayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The obtained residue was purified by silica gel column chromatography togive the title compound as a colorless solid (0.48 g, 69%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.4 Hz, 3H) 1.43-1.85 (m,6H) 2.15-2.27 (m, 5H) 2.59-2.78 (m, 2H) 2.98-3.08 (m, 2H) 3.40-3.54 (m,1H) 4.01 (s, 2H) 4.09 (s, 2H) 5.00-5.14 (m, 1H) 7.34-7.52 (m, 6H)7.58-7.66 (m, 1H) 7.75 (d, J=7.6 Hz, 1H) 7.91 (s, 1H)

Reference Example 2134′-({4-[trans-4-(2-{[tert-butyl(dimethyl)silyl]oxy}propoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a mixture of4′-({5-oxo-4-[trans-4-(2-oxopropoxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.48 g), methanol (5 mL) and tetrahydrofuran (5 mL) was added sodiumborohydride (0.042 g), and the mixture was stirred at room temperaturefor 2 hr. After evaporation of the solvent under reduced pressure, theresidue was extracted with water and ethyl acetate. The obtained ethylacetate layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The obtained residue was dissolved in tetrahydrofuran (5 mL),2,6-lutidine (0.16 mL) and tert-butyl(dimethyl)silyltrifluoromethanesulfonate (0.32 mL) were added, and the mixture wasstirred at room temperature for 1 hr. The reaction mixture was dilutedwith ethyl acetate, washed with water and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.45 g,77%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.08 (s, 6H) 0.90 (s, 9H) 1.07 (t,J=7.4 Hz, 3H) 1.14 (d, J=6.1 Hz, 3H) 1.32-1.52 (m, 2H) 1.67-1.84 (m, 4H)2.14-2.25 (m, 2H) 2.60-2.78 (m, 2H) 3.04 (dd, J=10.4, 5.5 Hz, 2H)3.22-3.51 (m, 1H) 3.36-3.48 (m, 2H) 3.85-3.95 (m, 1H) 4.02 (s, 2H)4.99-5.15 (m, 1H) 7.34-7.52 (m, 6H) 7.60-7.67 (m, 1H) 7.75 (d, J=8.0 Hz,1H) 7.92 (s, 1H)

Reference Example 2144′-({5-oxo-7-propyl-4-[(3a′R,6a′S)-tetrahydro-3a′H-spiro[cyclohexane-1,2′-cyclopenta[d][1,3]dioxol]-4-yl]-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.75 g), cyclopentane-1,2-diol (0.42 g), p-toluenesulfonic acidmonohydrate (0.018 g) and toluene (30 mL) was subjected to an azeotropicdehydration reaction by stirring at 110° C. for 16 hr in a reactionvessel equipped with a Dean-stark trap. The reaction mixture wasconcentrated, and the obtained residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (1.2 g,100%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.3 Hz, 3H), 1.33-1.59 (m,4H), 1.65-2.10 (m, 10H), 2.80-3.06 (m, 4H), 4.02 (s, 2H), 4.60-4.70 (m,2H), 5.00-5.14 (m, 1H), 7.34-7.52 (m, 6H), 7.59-7.67 (m, 1H), 7.75 (dd,J=7.7, 0.9 Hz, 1H), 7.95 (s, 1H)

Reference Example 2154′-{[4-(trans-4-{[(1R,2S)-2-hydroxycyclopentyl]oxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-({5-oxo-7-propyl-4-[(3a′R,6a′S)-tetrahydro-3a′H-spiro[cyclohexane-1,2′-cyclopenta[d][1,3]dioxol]-4-yl]-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(1.2 g), sodium cyanoborohydride (0.65 g), boron trifluoride-diethylether complex (1.3 mL) and tetrahydrofuran (30 mL) was stirred at 70° C.for 16 hr. The reaction mixture was diluted with ethyl acetate, washedwith water and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.82 g, 72%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.3 Hz, 3H), 1.39-1.89 (m,12H), 2.11-2.25 (m, 2H), 2.62-2.81 (m, 2H), 2.99-3.07 (m, 2H), 3.38-3.45(m, 1H), 3.48-3.59 (m, 1H), 3.81-3.89 (m, 1H), 3.98-4.06 (m, 2H),4.99-5.15 (m, 1H), 7.34-7.51 (m, 6H), 7.59-7.67 (m, 1H), 7.72-7.77 (m,1H), 7.92 (s, 1H)

Reference Example 2162-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide

A mixture of ethyl[(4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate(3.6 g), 1N aqueous sodium hydroxide solution (50 mL), methanol (50 mL)and tetrahydrofuran (50 mL) was stirred at room temperature for 3 hr.The reaction mixture was adjusted to pH 4 with water (20 mL) and 1 Nhydrochloric acid and extracted with ethyl acetate. The obtained residuewas dissolved in N,N-dimethylformamide (30 mL), N-methoxymethanaminehydrochloride (0.92 g), 1-hydroxybenzotriazole (1.5 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.8 g) andtriethylamine (1.3 mL) were added, and the mixture was stirred at roomtemperature for 16 hr. The reaction mixture was diluted with ethylacetate, washed with 1 N hydrochloric acid and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (1.1 g, 33%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.05 (t, J=7.25 Hz, 3H) 1.43-1.84 (m,6H) 2.20-2.31 (m, 2H) 2.43 (s, 3H) 2.64-2.81 (m, 2H) 2.92-3.01 (m, 2H)3.20 (s, 3H) 3.52-3.63 (m, 1H) 3.70 (s, 3H) 3.98 (s, 2H) 4.33 (s, 2H)4.94-5.11 (m, 1H) 7.31-7.52 (m, 6H) 7.58-7.68 (m, 1H) 7.74 (dd, J=7.72,0.94 Hz, 1H)

Reference Example 2174′-({2-methyl-5-oxo-4-[trans-4-(2-oxopropoxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

2-[(trans-4-{6-[(2′-Cyanobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide(1 g) was dissolved in tetrahydrofuran (15 mL), and methylmagnesiumbromide (1.0 M tetrahydrofuran solution, 1.7 mL) was added at roomtemperature. The reaction mixture was stirred for 1 hr, 1 N hydrochloricacid was added, and the mixture was extracted with ethyl acetate. Theobtained ethyl acetate layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.56 g,60%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.05 (t, J=7.3 Hz, 3H) 1.41-1.58 (m,2H) 1.66-1.84 (m, 4H) 2.13-2.24 (m, 5H) 2.43 (s, 3H) 2.62-2.79 (m, 2H)2.94-3.02 (m, 2H) 3.40-3.53 (m, 1H) 3.98 (s, 2H) 4.10 (s, 2H) 4.94-5.09(m, 1H) 7.32-7.51 (m, 6H) 7.59-7.66 (m, 1H) 7.75 (dd, J=7.7, 0.9 Hz, 1H)

Reference Example 2184′-[(4-{trans-4-[(2-{[tert-butyl(dimethyl)silyl]oxy}prop-2-en-1-yl)oxy]cyclohexyl}-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

To a solution (10 mL) of4′-({2-methyl-5-oxo-4-[trans-4-(2-oxopropoxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.56 g) and diisopropylethylamine (0.36 mL) in methylene chloride wasadded tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.36 mL), andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueoussodium hydrogen carbonate and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.5 g,72%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.18 (s, 6H) 0.94 (s, 9H) 1.05 (t,J=7.3 Hz, 3H) 1.39-1.56 (m, 2H) 1.65-1.82 (m, 4H) 2.13-2.23 (m, 2H) 2.44(s, 3H) 2.63-2.80 (m, 2H) 2.93-3.03 (m, 2H) 3.42-3.56 (m, 1H) 3.86 (s,2H) 3.99 (s, 2H) 4.24 (s, 1H) 4.39 (s, 1H) 4.92-5.09 (m, 1H) 7.33-7.51(m, 6H) 7.59-7.67 (m, 1H) 7.75 (dd, J=7.7, 0.9 Hz, 1H)

Reference Example 2194′-[(4-{trans-4-[(1-{[tert-butyl(dimethyl)silyl]oxy}cyclopropyl)methoxy]cyclohexyl}-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

To a solution (10 mL) of diethylzinc (1.0 M hexane solution, 5.3 mL) inmethylene chloride was added a solution (5 mL) of chloro(iodo)methane(0.38 mL) in methylene chloride at 0° C., and the mixture was stirred atthe same temperature for 10 min. A solution (5 mL) of4′-[(4-{trans-4-[(2-{[tert-butyl(dimethyl)silyl]oxy}prop-2-en-1-yl)oxy]cyclohexyl}-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.5 g) in methylene chloride was added to the reaction mixture, and themixture was further stirred at room temperature for 3 hr. Saturatedaqueous ammonium chloride solution was added to the reaction mixture,and the mixture was extracted with ethyl acetate. The obtained ethylacetate layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The obtained residue was purified by silica gel column chromatography togive the title compound as a colorless solid (0.26 g, 52%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.13 (s, 6H) 0.55-0.62 (m, 2H)0.70-0.77 (m, 2H) 0.85 (s, 9H) 1.05 (t, J=7.3 Hz, 3H) 1.37-1.55 (m, 2H)1.66-1.83 (m, 4H) 2.13-2.23 (m, 2H) 2.44 (s, 3H) 2.62-2.80 (m, 2H)2.93-3.02 (m, 2H) 3.37-3.49 (m, 3H) 3.99 (s, 2H) 5.00 (t, J=12.6 Hz, 1H)7.33-7.51 (m, 6H) 7.59-7.67 (m, 1H) 7.72-7.78 (m, 1H)

Reference Example 2204′-({4-[trans-4-(2-{[tert-butyl(dimethyl)silyl]oxy}propoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a mixture of4′-({2-methyl-5-oxo-4-[trans-4-(2-oxopropoxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.33 g), methanol (5 mL) and tetrahydrofuran (5 mL) was added sodiumborohydride (0.034 g), and the mixture was stirred at room temperaturefor 2 hr. After evaporation of the solvent under reduced pressure, theresidue was extracted with water and ethyl acetate. The obtained ethylacetate layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The obtained residue was dissolved in tetrahydrofuran (5 mL),2,6-lutidine (0.11 mL) and tert-butyl(dimethyl)silyltrifluoromethanesulfonate (0.21 mL) were added, and the mixture wasstirred at room temperature for 1 hr. The reaction mixture was dilutedwith ethyl acetate, washed with water and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.27 g,67%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.08 (s, 6H) 0.90 (s, 9H) 1.05 (t,J=7.3 Hz, 3H) 1.15 (d, J=6.2 Hz, 3H) 1.35-1.51 (m, 2H) 1.64-1.82 (m, 4H)2.13-2.23 (m, 2H) 2.44 (s, 3H) 2.62-2.80 (m, 2H) 2.92-3.02 (m, 2H)3.24-3.31 (m, 1H) 3.37-3.49 (m, 2H) 3.87-3.96 (m, 1H) 3.99 (s, 2H) 5.00(t, J=12.2 Hz, 1H) 7.33-7.52 (m, 6H) 7.59-7.66 (m, 1H) 7.75 (dd, J=7.7,0.9 Hz, 1H)

Reference Example 2214′-({2-methyl-5-oxo-4-[trans-4-(2-oxobutoxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

2-[(trans-4-{6-[(2′-Cyanobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide(0.3 g) was dissolved in tetrahydrofuran (10 mL), and ethylmagnesiumbromide (3.0 M diethyl ether solution, 0.52 mL) was added at roomtemperature. The reaction mixture was stirred for 1 hr, 1 N hydrochloricacid was added, and the mixture was extracted with ethyl acetate. Theobtained ethyl acetate layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.34 g,100%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.01-1.11 (m, 6H) 1.41-1.85 (m, 6H)2.14-2.24 (m, 2H) 2.43 (s, 3H) 2.52 (q, J=7.2 Hz, 2H) 2.63-2.81 (m, 2H)2.93-3.02 (m, 2H) 3.39-3.53 (m, 1H) 3.98 (s, 2H) 4.11 (s, 2H) 4.95-5.08(m, 1H) 7.33-7.50 (m, 6H) 7.59-7.66 (m, 1H) 7.74 (dd, J=7.7, 0.9 Hz, 1H)

Reference Example 2224′-({4-[trans-4-(2-{[tert-butyl(dimethyl)silyl]oxy}butoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a mixture of4′-({2-methyl-5-oxo-4-[trans-4-(2-oxobutoxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.34 g), methanol (5 mL) and tetrahydrofuran (5 mL) was added sodiumborohydride (0.035 g), and the mixture was stirred at room temperaturefor 2 hr. After evaporation of the solvent under reduced pressure, theresidue was extracted with water and ethyl acetate. The obtained ethylacetate layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The obtained residue was dissolved in tetrahydrofuran (5 mL),2,6-lutidine (0.10 mL) and tert-butyl(dimethyl)silyltrifluoromethanesulfonate (0.21 mL) were added, and the mixture wasstirred at room temperature for 1 hr. The reaction mixture was dilutedwith ethyl acetate, washed with water and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.29 g,71%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.08 (s, 6H) 0.90 (s, 12H) 1.05 (t,J=7.3 Hz, 3H) 1.32-1.81 (m, 8H) 2.12-2.23 (m, 2H) 2.44 (s, 3H) 2.63-2.80(m, 2H) 2.94-3.02 (m, 2H) 3.30-3.48 (m, 3H) 3.66-3.75 (m, 1H) 3.99 (s,2H) 4.93-5.07 (m, 1H) 7.33-7.53 (m, 6H) 7.59-7.67 (m, 1H) 7.72-7.78 (m,1H)

Reference Example 2234′-({4-[trans-4-(2-ethyl-2-hydroxybutoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

Ethyl[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate(0.5 g) was dissolved in tetrahydrofuran (10 mL), and ethylmagnesiumbromide (3.0 M diethyl ether solution, 0.75 mL) was added at 0° C. Afterstirring at the same temperature for 16 hr, 1 N hydrochloric acid wasadded to the reaction mixture, and the mixture was extracted with ethylacetate. The obtained ethyl acetate layer was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.25 g, 49%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.87 (t, J=7.5 Hz, 6H) 1.06 (t, J=7.3Hz, 3H) 1.34-1.56 (m, 6H) 1.65-1.84 (m, 4H) 2.11-2.22 (m, 2H) 2.60-2.78(m, 2H) 2.97-3.08 (m, 2H) 3.34 (s, 2H) 3.42 (t, J=11.0 Hz, 1H) 4.01 (s,2H) 5.00-5.13 (m, 1H) 7.34-7.52 (m, 6H) 7.58-7.66 (m, 1H) 7.75 (dd,J=7.8, 0.8 Hz, 1H) 7.91 (s, 1H)

Reference Example 2244′-{[4-(6,13-dioxadispiro[3.2.5.2]tetradec-10-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]thiazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(3 g), cyclobutane-1,1-diyldimethanol (1.1 g), p-toluenesulfonic acidmonohydrate (0.036 g) and toluene (60 mL) was subjected to an azeotropicdehydration reaction by stirring at 110° C. for 16 hr in a reactionvessel equipped with a Dean-stark trap. The reaction mixture wasconcentrated under reduced pressure, and the obtained residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (3.7 g, 100%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.95 (t, J=7.3 Hz, 3H) 1.29-1.43 (m,2H) 1.46-1.65 (m, 4H) 1.67-1.91 (m, 6H) 2.22-2.34 (m, 2H) 2.60-2.80 (m,2H) 2.91-3.02 (m, 2H) 3.70 (d, J=8.1 Hz, 4H) 3.98 (s, 2H) 4.94 (t,J=12.2 Hz, 1H) 7.37-7.43 (m, 2H) 7.45-7.63 (m, 4H) 7.73-7.82 (m, 1H)7.92 (d, J=1.1 Hz, 1H) 8.20 (s, 1H)

Reference Example 2254′-{[4-(trans-4-{[1-(hydroxymethyl)cyclobutyl]methoxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-{[4-(6,13-dioxadispiro[3.2.5.2]tetradec-10-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(3.7 g), sodium cyanoborohydride (1.3 g), boron trifluoride-diethylether complex (2.5 mL) and tetrahydrofuran (50 mL) was stirred at 70° C.for 16 hr. The reaction mixture was diluted with ethyl acetate, washedwith water and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (1.8 g, 47%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.95 (t, J=7.3 Hz, 3H), 1.19-1.36 (m,2H), 1.48-1.86 (m, 10H), 2.05-2.16 (m, 2H), 2.52-2.69 (m, 2H), 2.92-3.02(m, 2H), 3.22-3.37 (m, 3H), 3.39 (s, 2H), 4.00 (s, 2H), 4.45 (t, J=5.0Hz, 1H), 4.82-5.00 (m, 1H), 7.36-7.43 (m, 2H), 7.46-7.63 (m, 4H),7.72-7.83 (m, 1H), 7.93 (dd, J=7.7, 0.9 Hz, 1H), 8.19 (s, 1H)

Reference Example 2264′-[(4-{trans-4-[(1-formylcyclobutyl)methoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

To a mixture of4′-{[4-(trans-4-{[1-(hydroxymethyl)cyclobutyl]methoxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.7 g), triethylamine (0.86 mL) and dimethyl sulfoxide (10 mL) wasadded a solution (5 mL) of sulfur trioxide-pyridine complex (0.59 g) indimethyl sulfoxide at room temperature, and the mixture was stirred for3 hr. The reaction mixture was poured into 1 N hydrochloric acid, andthe mixture was extracted with ethyl acetate. The obtained ethyl acetatelayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The obtained residue was purified by silica gel column chromatography togive the title compound as a colorless solid (0.7 g, 100%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.95 (t, J=7.3 Hz, 3H), 1.20-1.37 (m,2H), 1.53-1.96 (m, 8H), 2.03-2.23 (m, 4H), 2.52-2.68 (m, 2H), 2.92-3.01(m, 2H), 3.25-3.44 (m, 3 H), 3.99 (s, 2H), 4.90 (t, J=12.2 Hz, 1H),7.38-7.43 (m, 2H), 7.46-7.62 (m, 4H), 7.73-7.82 (m, 1H), 7.93 (dd,J=7.7, 0.9 Hz, 1H), 8.19 (s, 1H), 9.57 (s, 1H)

Reference Example 2271-{[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]methyl}cyclobutanecarboxylicacid

A mixture of4′-[(4-{trans-4-[(1-formylcyclobutyl)methoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.7 g), sodium chlorite (0.21 g), sodium dihydrogen phosphate (0.15 g),2-methyl-2-butene (0.53 mL), n-butanol (10 mL), tetrahydrofuran (5 mL)and water (5 mL) was stirred at room temperature for 16 hr. The reactionmixture was extracted with 1 N hydrochloric acid and ethyl acetate. Theobtained ethyl acetate layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.47 g,65%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.95 (t, J=7.3 Hz, 3H), 1.19-1.36 (m,2H), 1.53-1.94 (m, 8H), 2.03-2.29 (m, 4H), 2.52-2.66 (m, 2H), 2.92-3.01(m, 2H), 3.25-3.39 (m, 1H), 3.68 (s, 2H), 3.99 (s, 2H), 4.83-4.97 (m,1H), 7.37-7.44 (m, 2H), 7.45-7.61 (m, 4H), 7.72-7.82 (m, 1H), 7.92 (d,J=0.9 Hz, 1H), 8.19 (s, 1H), 12.13 (br.s., 1H)

Reference Example 2281-{[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]methyl}cyclobutanecarboxamide

A mixture of1-{[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]methyl}cyclobutanecarboxylicacid (0.4 g), 1-hydroxybenzotriazole ammonium salt (0.24 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.26 g) andN,N-dimethylformamide (10 mL) was stirred at room temperature for 15 hr.The reaction mixture was diluted with ethyl acetate, washed with 1 Nhydrochloric acid and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.37 g,93%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.2 Hz, 3H), 1.21-1.39 (m, 2H),1.51-1.92 (m, 8H), 2.04-2.28 (m, 4H), 2.52-2.66 (m, 2H), 2.91-3.01 (m,2H), 3.26-3.40 (m, 1H), 3.64 (s, 2H), 3.99 (s, 2H), 4.91 (t, J=12.3 Hz,1H), 6.80 (s, 1H), 6.93 (s, 1H), 7.37-7.43 (m, 2H), 7.45-7.62 (m, 4H),7.77 (t, J=7.8 Hz, 1H), 7.93 (t, J=7.6 Hz, 1H), 8.19 (s, 1H)

Reference Example 2294′-{[4-(trans-4-{[1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclobutyl]methoxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

To a mixture of4′-{[4-(trans-4-{[1-(hydroxymethyl)cyclobutyl]methoxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.3 g), 2,6-lutidine (0.14 mL) and tetrahydrofuran (10 mL) was addedtert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.18 mL), and themixture was stirred at room temperature for 5 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.31 g,86%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.05 (s, 6H), 0.88 (s, 9H), 0.94 (t, J=7.4Hz, 3H), 1.21-1.36 (m, 2H), 1.51-1.86 (m, 10H), 2.04-2.15 (m, 2H),2.52-2.66 (m, 2H), 2.91-3.02 (m, 2H), 3.21-3.30 (m, 1H), 3.40 (s, 2H),3.51 (s, 2H), 3.99 (s, 2H), 4.91 (t, J=12.1 Hz, 1H), 7.37-7.43 (m, 2H),7.46-7.62 (m, 4H), 7.73-7.83 (m, 1H), 7.93 (d, J=6.8 Hz, 1H), 8.18 (s,1H)

Reference Example 2304′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-2′-fluorobiphenyl-2-carbonitrile

A mixture of ethyl2-[(2′-cyano-2-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (3.3 g) andN-(1,4-dioxaspiro[4.5]dec-8-yl)-4H-1,2,4-triazol-3-amine (1 g) wasstirred at 250° C. for 1 hr under microwave irradiation. The reactionmixture was purified by silica gel column chromatography to give thetitle compound as a colorless solid (1.2 g, 50%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.96 (t, J=7.3 Hz, 3H), 1.52-1.84 (m, 8H),2.71-2.88 (m, 2H), 2.92-3.01 (m, 2H), 3.83-3.97 (m, 4H), 4.02 (s, 2H),4.98 (t, J=12.5 Hz, 1H), 7.24-7.45 (m, 3H), 7.55-7.66 (m, 2H), 7.81 (t,J=7.1 Hz, 1H), 7.96 (dd, J=7.7, 0.9 Hz, 1H), 8.20 (s, 1H)

Reference Example 2312′-fluoro-4′-{[4-(4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-2′-fluorobiphenyl-2-carbonitrile(1.2 g), 3N hydrochloric acid (50 mL) and tetrahydrofuran (50 mL) wasstirred at 80° C. for 16 hr. The reaction mixture was diluted with ethylacetate, washed with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure. The obtainedresidue was dissolved in tetrahydrofuran (10 mL) and methanol (10 mL),sodium borohydride (0.17 g) was added, and the mixture was stirred atroom temperature for 1 hr. After evaporation of the solvent underreduced pressure, the residue was extracted with water and ethylacetate. The obtained ethyl acetate layer was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.95 g, 88%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.95 (t, J=7.3 Hz, 3H) 1.21-1.71 (m,6H) 1.88-1.99 (m, 2H) 2.52-2.65 (m, 2H) 2.92-3.01 (m, 2H) 3.41-3.54 (m,1H) 4.02 (s, 2H) 4.64 (d, J=4.5 Hz, 1H) 4.87 (t, J=12.2 Hz, 1H)7.21-7.45 (m, 3H) 7.55-7.66 (m, 2H) 7.76-7.85 (m, 1H) 7.96 (d, J=7.7,0.9 Hz, 1H) 8.19 (s, 1H)

Reference Example 2322′-fluoro-4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a mixture of2′-fluoro-4′-{[4-(4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.95 g), rhodium(I) acetate (0.007 g) and toluene (20 mL) was addeddropwise ethyl diazoacetate (0.96 mL) at 80° C., and the mixture wasstirred at the same temperature for 1 hr. The reaction mixture wasconcentrated, and the obtained residue was purified by silica gel columnchromatography. The obtained residue was dissolved in tetrahydrofuran(15 mL), and methylmagnesium bromide (1.0 M tetrahydrofuran solution,5.8 mL) was added at room temperature. The reaction mixture was stirredfor 1 hr, 1 N hydrochloric acid was added, and the mixture was extractedwith ethyl acetate. The obtained ethyl acetate layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography to give the title compound as acolorless solid (0.25 g, 23%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.3 Hz, 3H), 1.07 (s, 6H),1.22-1.38 (m, 2H), 1.53-1.77 (m, 4H), 2.06-2.15 (m, 2H), 2.52-2.68 (m,2H), 2.92-3.01 (m, 2H), 3.20 (s, 2H), 3.25-3.37 (m, 1H), 4.02 (s, 2H),4.22 (s, 1H), 4.82-4.99 (m, 1H), 7.22-7.45 (m, 3H), 7.54-7.66 (m, 2H),7.80 (t, J=7.7 Hz, 1H), 7.96 (dd, J=7.7, 0.9 Hz, 1H), 8.19 (s, 1H)

Reference Example 2334′-({7-butyl-4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a mixture of4′-{[7-butyl-4-(4-hydroxycyclohexyl)-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.61 g), rhodium(I) acetate (0.006 g) and toluene (30 mL) was addeddropwise ethyl diazoacetate (0.62 mL) at 80° C., and the mixture wasstirred at the same temperature for 1 hr. The reaction mixture wasconcentrated under reduced pressure, and the obtained residue waspurified by silica gel column chromatography. The obtained residue wasdissolved in tetrahydrofuran (15 mL), and methylmagnesium bromide (1.0 Mtetrahydrofuran solution, 1.9 mL) was added at room temperature. Thereaction mixture was stirred for 1 hr, 1 N hydrochloric acid was added,and the mixture was extracted with ethyl acetate. The obtained ethylacetate layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The obtained residue was purified by silica gel column chromatography togive the title compound as a colorless solid (0.22 g, 31%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.82 (t, J=7.2 Hz, 3H), 1.07 (s, 6H),1.21-1.56 (m, 6H), 1.65-1.76 (m, 2H), 2.06-2.16 (m, 2H), 2.53-2.65 (m,2H), 2.91-3.03 (m, 2H), 3.20 (s, 2 H), 3.99 (s, 2H), 4.23 (s, 1H), 4.92(t, J=12.4 Hz, 1H), 7.37-7.43 (m, 2H), 7.46-7.62 (m, 4H), 7.74-7.81 (m,1H), 7.91 (d, J=0.9 Hz, 1H), 8.18 (s, 1H)

Reference Example 2343′-fluoro-4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a mixture of3′-fluoro-4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.71 g), rhodium(I) acetate (0.006 g) and toluene (30 mL) was addeddropwise ethyl diazoacetate (0.71 mL) at 80° C., and the mixture wasstirred at the same temperature for 1 hr. The reaction mixture wasconcentrated under reduced pressure, and the obtained residue waspurified by silica gel column chromatography. The obtained residue wasdissolved in tetrahydrofuran (15 mL), and methylmagnesium bromide (1.0 Mtetrahydrofuran solution, 2.2 mL) was added at room temperature. Thereaction mixture was stirred for 1 hr, 1 N hydrochloric acid was added,and the mixture was extracted with ethyl acetate. The obtained ethylacetate layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The obtained residue was purified by silica gel column chromatography togive the title compound as a colorless solid (0.18 g, 22%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.3 Hz, 3H) 1.07 (s, 6H)1.21-1.37 (m, 2H) 1.56-1.75 (m, 4H) 2.04-2.16 (m, 2H) 2.51-2.65 (m, 2H)2.92-3.01 (m, 2H) 3.19 (s, 2H) 3.24-3.35 (m, 1H) 3.97 (s, 2H) 4.22 (s,1H) 4.81-4.97 (m, 1H) 7.25-7.49 (m, 3H) 7.55-7.68 (m, 2H) 7.75-7.83 (m,1H) 7.95 (dd, J=7.7, 0.9 Hz, 1H) 8.20 (s, 1H)

Reference Example 2354′-[(4-{trans-4-[2-(methylsulfanyl)ethoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

A mixture of4′-({4-[trans-4-(2-hydroxyethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.2 g), p-toluenesulfonyl chloride (0.089 g), triethylamine (0.066 mL),4-dimethylaminopyridine (0.005 g) and acetonitrile (10 mL) was stirredfor 4 hr. The reaction mixture was washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The obtained residue wasdissolved in acetonitrile (15 mL), sodium thiomethylate (15% aqueoussolution, 1.8 g) was added, and the mixture was stirred at 50° C. for 16hr. The reaction mixture was diluted with ethyl acetate, washed withwater and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.2 g, 94%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.3 Hz, 3H), 1.21-1.37 (m, 2H),1.52-1.76 (m, 4H), 2.05-2.15 (m, 5H), 2.55-2.68 (m, 4H), 2.91-3.02 (m,2H), 3.32-3.41 (m, 1H), 3.61 (t, J=6.8 Hz, 2H), 3.99 (s, 2H), 4.82-4.99(m, 1H), 7.38-7.44 (m, 2H), 7.46-7.62 (m, 4H), 7.73-7.82 (m, 1H), 7.92(d, J=0.8 Hz, 1H), 8.18 (s, 1H)

Reference Example 2362-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-1,1-dimethylethylacetate

A mixture of4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.2 g), acetic anhydride (5 mL) and pyridine (5 mL) was stirred at 120°C. for 6 hr. The reaction mixture was diluted with ethyl acetate, washedwith 1 N hydrochloric acid and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.1 g,47%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.3 Hz, 3H), 1.22-1.39 (m, 8H),1.51-1.74 (m, 4H), 1.93 (s, 3H), 2.03-2.14 (m, 2H), 2.36 (s, 3H),2.52-2.63 (m, 2H), 2.86-2.96 (m, 2H), 3.23-3.31 (m, 1H), 3.57 (s, 2H),3.97 (s, 2H), 4.81-4.95 (m, 1H), 7.35-7.43 (m, 2H), 7.45-7.62 (m, 4H),7.73-7.81 (m, 1H), 7.90-7.96 (m, 1H)

Reference Example 2374′-{[7-butyl-4-(1,4-dioxaspiro[4.5]dec-8-yl)-2-methyl-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate(15 g),N-(1,4-dioxaspiro[4.5]dec-8-yl)-5-methyl-4H-1,2,4-triazol-3-amine (5 g),1,8-diazabicyclo[5.4.0]undec-7-ene (1.4 mL) and N,N-diethylaniline (80mL) was stirred at 180° C. for 16 hr. The obtained reaction mixture wasdiluted with ethyl acetate, washed 3 times with 1 N hydrochloric acidand saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (6.4 g, 57%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (t, J=7.2 Hz, 3H), 1.28-1.84 (m, 10H),2.37 (s, 3H), 2.68-2.87 (m, 2H), 2.88-2.97 (m, 2H), 3.82-4.00 (m, 6H),4.93 (t, J=12.3 Hz, 1H), 7.36-7.42 (m, 2H), 7.44-7.61 (m, 4H), 7.73-7.83(m, 1H), 7.93 (d, J=8.0 Hz, 1H)

Reference Example 2384′-{[7-butyl-4-(trans-4-hydroxycyclohexyl)-2-methyl-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-{[7-butyl-4-(1,4-dioxaspiro[4.5]dec-8-yl)-2-methyl-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(6.4 g), 3N hydrochloric acid (40 mL) and tetrahydrofuran (40 mL) wasstirred at 80° C. for 16 hr. The reaction mixture was diluted with ethylacetate, washed with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure. The obtainedresidue was dissolved in tetrahydrofuran (30 mL) and methanol (30 mL),sodium borohydride (0.67 g) was added, and the mixture was stirred atroom temperature for 1 hr. After evaporation of the solvent underreduced pressure, the residue was extracted with water and ethylacetate. The obtained ethyl acetate layer was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (4.9 g, 83%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (t, J=7.2 Hz, 3H), 1.19-1.69 (m, 8H),1.88-2.00 (m, 2H), 2.36 (s, 3H), 2.51-2.64 (m, 2H), 2.87-2.97 (m, 2H),3.39-3.55 (m, 1H), 3.96 (s, 2H), 4.65 (d, J=4.2 Hz, 1H), 4.83 (t, J=11.9Hz, 1H), 7.34-7.42 (m, 2H), 7.45-7.62 (m, 4H), 7.78 (t, J=7.8 Hz, 1H),7.93 (d, J=7.2 Hz, 1H)

Reference Example 2394′-({7-butyl-4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-2-methyl-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a mixture of4′-{[7-butyl-4-(trans-4-hydroxycyclohexyl)-2-methyl-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.45 g), rhodium(I) acetate (0.004 g) and toluene (10 mL) was addeddropwise 3-ethoxy-2-methyl-3-oxopropane-1-diazonium (0.72 L) at 80° C.,and the mixture was stirred at the same temperature for 1 hr. Thereaction mixture was concentrated under reduced pressure, and theobtained residue was purified by silica gel column chromatography. Theobtained residue was dissolved in tetrahydrofuran (10 mL), andmethylmagnesium bromide (1.0 M tetrahydrofuran solution, 2.5 mL) wasadded at room temperature. The reaction mixture was stirred for 1 hr, 1N hydrochloric acid was added, and the mixture was extracted with ethylacetate. The obtained ethyl acetate layer was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.33 g, 63%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91-1.09 (m, 12H), 1.21-1.73 (m, 8H),2.01-2.15 (m, 2H), 2.36 (s, 3H), 2.52-2.66 (m, 2H), 2.85-2.97 (m, 2H),3.25 (q, J=6.1 Hz, 1H), 3.33-3.42 (m, 1H), 3.97 (s, 1H), 4.07 (s, 1H),4.79-4.93 (m, 1H), 7.38 (d, J=8.3 Hz, 2H), 7.45-7.61 (m, 4H), 7.73-7.82(m, 1H), 7.93 (d, J=7.6 Hz, 1H)

Reference Example 2403′-fluoro-4′-{[4-(trans-4-hydroxycyclohexyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile(14 g), 3N hydrochloric acid (50 mL) and tetrahydrofuran (50 mL) wasstirred at 80° C. for 16 hr. The reaction mixture was diluted with ethylacetate, washed with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure. The obtainedresidue was dissolved in tetrahydrofuran (40 mL) and methanol (40 mL),sodium borohydride (1.5 g) was added, and the mixture was stirred atroom temperature for 1 hr. After evaporation of the solvent underreduced pressure, the residue was extracted with water and ethylacetate. The obtained ethyl acetate layer was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (12 g, 93%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.2 Hz, 3H), 1.12-1.98 (m, 8H),2.37 (s, 3H), 2.50-2.62 (m, 2H), 2.85-2.98 (m, 2H), 3.38-3.55 (m, 1H),3.94 (s, 2H), 4.64 (d, J=4.5 Hz, 1H), 4.81 (t, J=12.1 Hz, 1H), 7.24-7.38(m, 2H), 7.45 (d, J=11.0 Hz, 1H), 7.54-7.67 (m, 2H), 7.79 (t, J=7.8 Hz,1H), 7.95 (d, J=7.6 Hz, 1H)

Reference Example 2413′-fluoro-4′-({4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a mixture of3′-fluoro-4′-{[4-(trans-4-hydroxycyclohexyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.46 g), rhodium(I) acetate (0.004 g) and toluene (10 mL) was addeddropwise 3-ethoxy-2-methyl-3-oxopropane-1-diazonium (0.69 mL) at 80° C.,and the mixture was stirred at the same temperature for 1 hr. Thereaction mixture was concentrated, and the obtained residue was purifiedby silica gel column chromatography. The obtained residue was dissolvedin tetrahydrofuran (10 mL), and methylmagnesium bromide (1.0 Mtetrahydrofuran solution, 2.5 mL) was added at room temperature. Thereaction mixture was stirred for 1 hr, 1 N hydrochloric acid was added,and the mixture was extracted with ethyl acetate. The obtained ethylacetate layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The obtained residue was purified by silica gel column chromatography togive the title compound as a colorless solid (0.27 g, 50%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90-1.10 (m, 12H), 1.21-1.38 (m, 2H),1.53-1.72 (m, 4H), 2.00-2.15 (m, 2H), 2.37 (s, 3H), 2.52-2.65 (m, 2H),2.86-2.96 (m, 2H), 3.24 (q, J=6.4 Hz, 1H), 3.34-3.42 (m, 1H), 3.94 (s,2H), 4.06 (s, 1H), 7.25-7.66 (m, 5H), 7.76-7.82 (m, 1H), 7.95 (d, J=7.6Hz, 1H)

Reference Example 2422-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]propanoicacid

To a mixture of4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(4 g), rhodium(I) acetate (0.028 g) and toluene (70 mL) was addeddropwise a solution (10 mL) of3-ethoxy-2-methyl-3-oxopropane-1-diazonium (5.5 mL) in toluene at 80°C., and the mixture was stirred at the same temperature for 1 hr. Thereaction mixture was concentrated, and the obtained residue was purifiedby silica gel column chromatography. The obtained residue was dissolvedin tetrahydrofuran (20 mL) and methanol (20 mL), and 1N aqueous sodiumhydroxide solution (20 mL) was added. The reaction mixture was stirredfor 1 hr, 1N aqueous hydrochloric acid solution was added, and themixture was extracted with ethyl acetate. The obtained ethyl acetatelayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The obtained residue was purified by silica gel column chromatography togive the title compound as a colorless solid (4.1 g, 89%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.4 Hz, 3H), 1.26 (d, J=6.8 Hz,3H), 1.37-1.75 (m, 6H), 2.20-2.18 (m, 2H), 2.51-2.65 (m, 2H), 2.91-3.02(m, 2H), 3.33-3.44 (m, 1H), 3.99 (s, 2H), 4.05-4.14 (m, 1H), 4.91 (t,J=12.1 Hz, 1H), 7.38-7.44 (m, 2H), 7.46-7.62 (m, 4H), 7.73-7.81 (m, 1H),7.93 (d, J=7.6 Hz, 1H), 8.18 (s, 1H), 12.47 (br.s., 1H)

Reference Example 2432-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]propanamide

A mixture of2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]propanoicacid (1.1 g), 1-hydroxybenzotriazole ammonium salt (0.42 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.47 g) andN,N-dimethylformamide (10 mL) was stirred at room temperature for 15 hr.The reaction mixture was diluted with ethyl acetate, washed with dilutehydrochloric acid and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.8 g,73%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.3 Hz, 3H), 1.21 (d, J=6.6 Hz,3H), 1.26-1.77 (m, 6H), 2.04-2.17 (m, 2H), 2.52-2.67 (m, 2H), 2.93-3.02(m, 2H), 3.30-3.40 (m, 1H), 3.90 (q, J=6.8 Hz, 1H), 4.00 (s, 2H),4.85-4.98 (m, 1H), 7.14 (s, 2H), 7.38-7.44 (m, 2H), 7.45-7.62 (m, 4H),7.74-7.82 (m, 1H), 7.89-7.98 (m, 1H), 8.18 (s, 1H)

Reference Example 2443′-fluoro-4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile(3.1 g), p-toluenesulfonic acid monohydrate (0.1 g), methanol (50 mL)and tetrahydrofuran (50 mL) was stirred at 60° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The obtained residue was dissolved inacetone (20 mL), 1 N hydrochloric acid (20 mL) was added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (2.1 g,76%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.08 (t, J=7.3 Hz, 3H) 1.65-1.81 (m,2H) 2.03-2.13 (m, 2H) 2.51-2.61 (m, 4H) 3.01-3.17 (m, 4H) 4.04 (s, 2H)5.49-5.62 (m, 1H) 7.22-7.29 (m, 2H) 7.36-7.52 (m, 3H) 7.61-7.68 (m, 1H)7.74-7.80 (m, 1H) 7.91 (s, 1H)

Reference Example 2453′-fluoro-4′-({5-oxo-7-propyl-4-[(3a′R,6a′S)-tetrahydrospiro[cyclohexane-1,2′-furo[3,4-d][1,3]dioxol]-4-yl]-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of3′-fluoro-4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(1 g), tetrahydrofuran-3,4-diol (0.26 g), p-toluenesulfonic acidmonohydrate (0.005 g) and toluene (50 mL) was subjected to an azeotropicdehydration reaction by stirring at 110° C. for 3 hr in a reactionvessel equipped with a Dean-stark trap. The reaction mixture wasconcentrated, and the obtained residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (1.3 g,100%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.35 Hz, 3H) 1.41-1.99 (m, 8H)2.65-2.87 (m, 2H) 2.92-3.01 (m, 2H) 3.32-3.39 (m, 2H) 3.78-4.00 (m, 4H)4.74-4.84 (m, 2H) 4.87-5.01 (m, 1H) 7.26-7.48 (m, 3H) 7.55-7.66 (m, 2H)7.75-7.83 (m, 1H) 7.95 (dd, J=7.72, 0.94 Hz, 1H) 8.22 (s, 1H)

Reference Example 2463′-fluoro-4′-{[4-(trans-4-{[(3R,4S)-4-hydroxytetrahydrofuran-3-yl]oxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of3′-fluoro-4′-({5-oxo-7-propyl-4-[(3a′R,6a′S)-tetrahydrospiro[cyclohexane-1,2′-furo[3,4-d][1,3]dioxol]-4-yl]-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(1.3 g), sodium cyanoborohydride (2.9 g), boron trifluoride-diethylether complex (5.9 mL) and tetrahydrofuran (50 mL) was stirred at 70° C.for 2 days. The reaction mixture was diluted with ethyl acetate, washedwith water and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.39 g, 30%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.4 Hz, 3H) 1.25-1.75 (m, 6H)2.07-2.22 (m, 2H) 2.53-2.67 (m, 2H) 2.91-3.02 (m, 2H) 3.28-4.15 (m, 9H)4.54 (d, J=5.1 Hz, 1H) 4.81-4.96 (m, 1H) 7.26-7.50 (m, 3H) 7.55-7.67 (m,2H) 7.75-7.84 (m, 1H) 7.92-8.00 (m, 1H) 8.20 (s, 1H)

Reference Example 2473′-fluoro-4′-{[5-oxo-4-(trans-4-{[(3R)-4-oxotetrahydrofuran-3-yl]oxy}cyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

3′-Fluoro-4′-{[4-(trans-4-{[(3R,4S)-4-hydroxytetrahydrofuran-3-yl]oxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.39 g) was dissolved in acetonitrile (10 mL),1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.45 g) wasadded, and the mixture was stirred at room temperature for 4 hr.Saturated aqueous sodium hydrogen carbonate solution and sodiumthiosulfate were added to the reaction mixture, and the mixture wasstirred at room temperature for 2 hr, and extracted with ethyl acetate.The organic layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.18 g,45%).

¹H NMR (300 MHz, DMSO-d₆) δ 1.07 (t, J=7.4 Hz, 3H) 1.41-1.90 (m, 6H)2.10-2.34 (m, 2H) 2.65-2.84 (m, 2H) 3.00-3.09 (m, 2H) 3.68-4.21 (m, 7H)4.38-4.47 (m, 1H) 4.99-5.15 (m, 1H) 7.22-7.30 (m, 2H) 7.34-7.52 (m, 3H)7.61-7.69 (m, 1H) 7.76 (d, J=7.6 Hz, 1H) 7.92 (s, 1H)

Reference Example 2483′-fluoro-4′-[(4-{trans-4-[(4-hydroxy-4-methyltetrahydrofuran-3-yl)oxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

3′-Fluoro-4′-{[5-oxo-4-(trans-4-{[(3R)-4-oxotetrahydrofuran-3-yl]oxy}cyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.18 g) was dissolved in tetrahydrofuran (10 mL), and methylmagnesiumbromide (1.0 M tetrahydrofuran solution, 0.95 mL) was added at roomtemperature. The reaction mixture was stirred for 3 hr, saturatedaqueous ammonium chloride solution was added to the reaction mixture,and the mixture was extracted with ethyl acetate. The obtained ethylacetate layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The obtained residue was purified by silica gel column chromatography togive the title compound as a colorless solid (0.077 g, 42%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.07 (t, J=7.3 Hz, 3H) 1.34 (s, 3H)1.42-1.87 (m, 6H) 2.06-2.27 (m, 2H) 2.62-2.80 (m, 2H) 3.00-3.09 (m, 3H)3.49-3.78 (m, 4H) 3.99-4.08 (m, 3H) 5.00-5.15 (m, 1H) 7.22-7.29 (m, 2H)7.33-7.50 (m, 3H) 7.64 (t, J=7.6 Hz, 1H) 7.66 (d, J=7.7 Hz, 1H) 7.91 (s,1H)

Reference Example 2494′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-4-fluorobiphenyl-2-carbonitrile

A mixture of ethyl2-[(2′-cyano-4′-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (2.9 g),N-(1,4-dioxaspiro[4.5]dec-8-yl)-5-methyl-4H-1,2,4-triazol-3-amine (0.93g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.29 mL) and N,N-diethylaniline(30 mL) was stirred at 180° C. for 16 hr. The obtained reaction mixturewas diluted with ethyl acetate, washed 3 times with 1 N hydrochloricacid and saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (1.1 g, 48%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.3 Hz, 3H) 1.51-1.84 (m, 8H)2.36 (s, 3H) 2.67-2.97 (m, 4H) 3.81-3.99 (m, 6H) 4.92 (t, J=12.4 Hz, 1H)7.36-7.50 (m, 4H) 7.57-7.72 (m, 2H) 7.94 (dd, J=8.7, 1.9 Hz, 1H)

Reference Example 2504′-{[4-(2,3-dimethyl-1,4-dioxaspiro[4.5]dec-8-yl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-4-fluorobiphenyl-2-carbonitrile

A mixture of4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-4-fluorobiphenyl-2-carbonitrile(1.1 g), 3N hydrochloric acid (30 mL) and tetrahydrofuran (30 mL) wasstirred at 70° C. for 16 hr. The reaction mixture was diluted with ethylacetate, washed with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure. The obtainedresidue was dissolved in toluene (30 mL), 2,3-dimethylpropane-1,3-diol(0.2 g) and p-toluenesulfonic acid monohydrate (0.004 g) were added, andthe mixture was subjected to an azeotropic dehydration reaction bystirring at 110° C. for 3 hr in a reaction vessel equipped with aDean-stark trap. The reaction mixture was concentrated under reducedpressure, and the obtained residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (1.3 g,100%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.4 Hz, 3H) 1.01-1.25 (m, 6H)1.37-1.97 (m, 8H) 2.36 (s, 3H) 2.66-2.84 (m, 2H) 2.87-2.97 (m, 2H)3.54-4.30 (m, 4H) 4.87 (t, J=12.5 Hz, 1H) 7.34-7.51 (m, 4H) 7.59-7.72(m, 2H) 7.94 (dd, J=8.5, 2.1 Hz, 1H)

Reference Example 2514′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

To a solution of N-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazol-5-amine(11.8 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.6 mL) inN,N-diethylaniline (60 mL) was added dropwise a solution of ethyl2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (24 g) inN,N-diethylaniline (40 mL) at 180° C. The mixture was stirred for 3 hrand allowed to cool to room temperature, and ethyl acetate and waterwere added. The mixture was extracted with ethyl acetate, and theorganic layer was successively washed with water and saturated brine,dried over anhydrous magnesium sulfate, and concentrated. The residuewas purified by silica gel column chromatography to give the titlecompound as a pale-yellow amorphous solid (19.5 g, 73%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.5 Hz, 3H), 1.65-1.92 (m,8H), 2.48-2.68 (m, 2H), 3.02-3.12 (m, 2H), 3.94-4.06 (m, 6H), 5.23 (br.s., 1H), 6.18 (d, J=2.1 Hz, 1 H), 7.34-7.48 (m, 6H), 7.56-7.64 (m, 1H),7.68-7.75 (m, 2H)

Reference Example 2524-fluoro-4′-({4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-{[4-(2,3-dimethyl-1,4-dioxaspiro[4.5]dec-8-yl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-4-fluorobiphenyl-2-carbonitrile(1.3 g), sodium cyanoborohydride (0.71 g), boron trifluoride-diethylether complex (1.4 mL) and tetrahydrofuran (30 mL) was stirred at 40° C.for 40 hr. The reaction mixture was diluted with ethyl acetate, washedwith water and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The residue obtained by purification by silica gel column chromatographywas dissolved in acetonitrile (20 mL),1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.96 g) wasadded, and the mixture was stirred at room temperature for 4 hr.Saturated aqueous sodium hydrogen carbonate solution and sodiumthiosulfate were added to the reaction mixture, and the mixture wasstirred at room temperature for 2 hr, and extracted with ethyl acetate.The organic layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The residue obtained by purification by silica gel columnchromatography was dissolved in tetrahydrofuran (10 mL), andmethylmagnesium bromide (1.0 M tetrahydrofuran solution, 0.65 mL) wasadded at room temperature. The reaction mixture was stirred for 3 hr,saturated aqueous ammonium chloride solution was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The obtainedethyl acetate layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.24 g,18%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.2 Hz, 3H) 1.14-1.21 (m, 9H)1.25-1.74 (m, 6H) 2.04-2.13 (m, 2H) 2.35 (s, 3 H) 2.52-2.64 (m, 2H)2.86-2.96 (m, 2H) 3.22-3.40 (m, 1H) 3.93-4.09 (m, 3H) 4.88 (t, J=11.9Hz, 1H) 7.35-7.49 (m, 4H) 7.59-7.71 (m, 2H) 7.94 (dd, J=8.7, 2.3 Hz, 1H)

Reference Example 2532-[(trans-4-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]propanamide

To a mixture of3′-fluoro-4′-{[4-(trans-4-hydroxycyclohexyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(1 g), rhodium(I) acetate (0.009 g) and toluene (20 mL) was addeddropwise 3-ethoxy-2-methyl-3-oxopropane-1-diazonium (1.5 mL) at 80° C.,and the mixture was stirred at the same temperature for 1 hr. Thereaction mixture was concentrated, and the residue obtained bypurification by silica gel column chromatography was dissolved intetrahydrofuran (10 mL) and methanol (10 mL). 1N Aqueous sodiumhydroxide solution (10 mL) was added, and the mixture was stirred atroom temperature for 3 hr. 1 N Hydrochloric acid was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theobtained ethyl acetate layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The obtained residue was dissolved inN,N-dimethylformamide (10 mL), 1-hydroxybenzotriazole ammonium salt(0.21 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(0.3 g) were added, and the mixture was stirred at room temperature for16 hr. The reaction mixture was diluted with ethyl acetate, washed withdilute hydrochloric acid and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.37 g,65%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H) 1.18-1.47 (m, 5H)1.53-1.74 (m, 4H) 2.04-2.17 (m, 2H) 2.37 (s, 3H) 2.49-2.64 (m, 2H)2.88-2.96 (m, 2H) 3.27-3.41 (m, 1H) 3.85-3.98 (m, 3H) 4.87 (t, J=12.2Hz, 1H) 7.14 (br. s., 2H) 7.25-7.48 (m, 3H) 7.56-7.65 (m, 2H) 7.75-7.83(m, 1H) 7.95 (d, J=7.3 Hz, 1H)

Reference Example 2544′-{[4-(6,13-dioxadispiro[3.2.5.2]tetradec-10-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile

A mixture of3′-fluoro-4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(3.5 g), cyclobutane-1,1-diyldimethanol (1 g), p-toluenesulfonic acidmonohydrate (0.014 g) and toluene (60 mL) was subjected to an azeotropicdehydration reaction by stirring at 110° C. for 16 hr in a reactionvessel equipped with a Dean-stark trap. The reaction mixture wasconcentrated, and the obtained residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (3.6 g,86%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.3 Hz, 3H), 1.28-1.90 (m, 12H),2.28 (d, J=13.2 Hz, 2H), 2.59-2.77 (m, 2H), 2.91-3.01 (m, 2H), 3.70 (d,J=8.1 Hz, 4H), 3.97 (s, 2H), 4.83-5.01 (m, 1H), 7.25-7.48 (m, 3H),7.55-7.66 (m, 2H), 7.75-7.84 (m, 1H), 7.95 (dd, J=7.7, 0.9 Hz, 1H), 8.21(s, 1H)

Reference Example 2553′-fluoro-4′-{[4-(trans-4-{[1-(1-hydroxyethyl)cyclobutyl]methoxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-{[4-(6,13-dioxadispiro[3.2.5.2]tetradec-10-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile(3.6 g), sodium cyanoborohydride (5.3 g), boron trifluoride-diethylether complex (3.1 mL) and tetrahydrofuran (150 mL) was stirred at 50°C. for 24 hr. The reaction mixture was diluted with ethyl acetate,washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The residue obtained by purification by silica gel columnchromatography was dissolved in acetonitrile (30 mL),1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (3.4 g) wasadded, and the mixture was stirred at room temperature for 4 hr.Saturated aqueous sodium hydrogen carbonate solution and sodiumthiosulfate were added to the reaction mixture, and the mixture wasstirred at room temperature for 2 hr, and extracted with ethyl acetate.The organic layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The residue obtained by purification by silica gel columnchromatography was dissolved in tetrahydrofuran (20 mL), andmethylmagnesium bromide (1.0 M tetrahydrofuran solution, 4.5 mL) wasadded at room temperature. The reaction mixture was stirred for 2 hr,saturated aqueous ammonium chloride solution was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The obtainedethyl acetate layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.72 g,19%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91-1.00 (m, 5H) 1.21-1.37 (m, 2H)1.49-2.17 (m, 12H) 2.51-2.66 (m, 2H) 2.91-3.02 (m, 2H) 3.22-3.32 (m, 1H)3.36-3.52 (m, 2H) 3.57-3.67 (m, 1H) 3.98 (s, 2H) 4.28 (d, J=5.30 Hz, 1H)4.90 (t, J=12.12 Hz, 1H) 7.26-7.39 (m, 2H) 7.42-7.49 (m, 1H) 7.55-7.66(m, 2H) 7.75-7.83 (m, 1H) 7.95 (d, J=7.57 Hz, 1H) 8.20 (s, 1H)

Reference Example 2564′-[(4-{trans-4-[(1-acetylcyclobutyl)methoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile

3′-Fluoro-4′-{[4-(trans-4-{[1-(1-hydroxyethyl)cyclobutyl]methoxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.72 g) was dissolved in acetonitrile (20 mL),1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.77 g) wasadded, and the mixture was stirred at room temperature for 4 hr.Saturated aqueous sodium hydrogen carbonate solution and sodiumthiosulfate were added to the reaction mixture, and the mixture wasstirred at room temperature for 2 hr, and extracted with ethyl acetate.The organic layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.65 g,89%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.38 Hz, 3H) 1.18-1.34 (m, 2H)1.54-1.95 (m, 8H) 2.03-2.13 (m, 5H) 2.17-2.29 (m, 2H) 2.52-2.64 (m, 2H)2.91-3.01 (m, 2H) 3.25-3.39 (m, 1H) 3.77 (s, 2H) 3.97 (s, 2H) 4.81-4.96(m, 1H) 7.25-7.39 (m, 2H) 7.42-7.50 (m, 1H) 7.55-7.67 (m, 2H) 7.75-7.83(m, 1H) 7.95 (d, J=7.57 Hz, 1H) 8.20 (s, 1H)

Reference Example 2573′-fluoro-4′-[(4-{trans-4-[(1-hydroxycyclobutyl)methoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

To a mixture of4′-[(4-{trans-4-[(1-acetylcyclobutyl)methoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile(0.3 g), 30% hydrogen peroxide water (2.1 g) and chloroform (10 mL) wasgradually added trifluoroacetic acid anhydride (2.1 mL) at roomtemperature, and the reaction mixture was warmed to 60° C. and stirredfor 24 hr. Saturated aqueous sodium hydrogen carbonate and sodiumthiosulfate were added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The obtained residue wasdissolved in tetrahydrofuran (5 mL) and methanol (5 mL), 1N aqueoussodium hydroxide solution (5 mL) was added, and the mixture was stirredat room temperature for 30 min. 1N Aqueous hydrochloric acid solutionwas added to the reaction mixture, and the mixture was extracted withethyl acetate. The ethyl acetate layer was washed with saturated brine,and dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography to give the title compound as a colorless solid(0.19 g, 65%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.2 Hz, 3H) 1.21-1.76 (m, 8H)1.80-2.19 (m, 6H) 2.51-2.66 (m, 2H) 2.92-3.01 (m, 2H) 3.32-3.43 (m, 3H)3.97 (s, 2H) 4.81-4.97 (m, 2H) 7.26-7.49 (m, 3H) 7.55-7.66 (m, 2H)7.75-7.84 (m, 1 H) 7.95 (d, J=6.8 Hz, 1H) 8.20 (s, 1H)

Reference Example 258 propyl 3-methylidenecyclobutanecarboxylate

A mixture of 3-methylidenecyclobutanecarboxylic acid (18 g), sodiumhydride (6.9 g) and N,N-dimethylformamide (300 mL) was stirred at roomtemperature for 10 min, propyl iodide (17 mL) was added, and the mixturewas stirred at room temperature for 16 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 5% aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by distillation (45-50° C., 2mmHg) to give the title compound as a colorless oil (16 g, 66%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.88 (t, J=7.4 Hz, 3H) 1.52-1.65 (m, 2H)2.78-2.94 (m, 4H) 3.08-3.23 (m, 1H) 4.00 (t, J=6.7 Hz, 2H) 4.76-4.83 (m,2H)

Reference Example 259 propyl 3-oxocyclobutanecarboxylate

An ozone gas was blown into a solution (200 mL) of propyl3-methylidenecyclobutanecarboxylate (15 g) in methanol at −78° C. for 2hr. Dimethyl sulfide (21 g) was added to the reaction mixture at thesame temperature, and the mixture was warmed to room temperature over 1hr. The obtained mixture was concentrated and purified by silica gelcolumn chromatography to give the title compound as a colorless oil (13g, 88%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.4 Hz, 3H) 1.54-1.69 (m, 2H)3.17-3.40 (m, 5H) 4.04 (t, J=6.2 Hz, 2H)

Reference Example 260 propyl3-(4H-1,2,4-triazol-3-ylamino)cyclobutanecarboxylate

To a solution (100 mL) of 1H-1,2,4-triazol-3-amine (6.7 g) and propyl3-oxocyclobutanecarboxylate (14 g) in acetic acid was added sodiumcyanoborohydride (14 g), and the mixture was stirred at room temperaturefor 16 hr. Water was added to the reaction mixture, and the solvent wasevaporated under reduced pressure. The obtained residue was poured intosaturated aqueous sodium hydrogen carbonate, and the mixture wasextracted with a mixed solvent of ethyl acetate and isopropyl alcohol(3:1). The obtained extract was dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (8.8 g, 49%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83-0.93 (m, 3H) 1.50-1.66 (m, 2H)2.00-2.58 (m, 4H) 2.70-3.08 (m, 1H) 3.82-4.19 (m, 3H) 6.67-7.57 (m, 1H)11.79-13.06 (m, 1H)

Reference Example 261 propyl3-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclobutanecarboxylate

A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (12g), propyl 3-(4H-1,2,4-triazol-3-ylamino)cyclobutanecarboxylate (4 g),1,8-diazabicyclo[5.4.0]undec-7-ene (1.2 mL) and N,N-diethylaniline (50mL) was stirred at 180° C. for 16 hr. The obtained reaction mixture wasdiluted with ethyl acetate, washed 3 times with 1 N hydrochloric acidand saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas a mixture of geometric isomers (5 g, 55%).

A trans form: ¹H NMR (300 MHz, CHLOROFORM-d) δ 0.97 (t, J=7.38 Hz, 3H)1.06 (t, J=7.38 Hz, 3H) 1.63-1.80 (m, 4H) 2.61-2.73 (m, 2H) 2.99-3.08(m, 2H) 3.32-3.52 (m, 3H) 4.02 (s, 2H) 4.11 (t, J=6.63 Hz, 2H) 5.82-5.95(m, 1H) 7.35-7.52 (m, 6H) 7.59-7.66 (m, 1H) 7.74 (d, J=7.95 Hz, 1H) 7.95(s, 1H)A cis form: ¹H NMR (300 MHz, CHLOROFORM-d) δ 0.97 (t, J=7.38 Hz, 3H)1.05 (t, J=7.38 Hz, 3H) 1.61-1.79 (m, 4H) 2.61-2.76 (m, 2H) 2.87-3.09(m, 3H) 3.37-3.53 (m, 2H) 4.02 (s, 2H) 4.06-4.16 (m, 2H) 5.31-5.48 (m,1H) 7.36-7.52 (m, 6H) 7.58-7.66 (m, 1H) 7.73 (d, J=7.57 Hz, 1H) 7.93 (s,1H)

Reference Example 2624′-{[4-(trans-3-acetylcyclobutyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of propyl3-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclobutanecarboxylate(5 g), 1N aqueous sodium hydroxide solution (10 mL), methanol (10 mL)and tetrahydrofuran (10 mL) was stirred at room temperature for 2 hr.The reaction mixture was adjusted to pH 4 with water and 1 Nhydrochloric acid, and extracted with ethyl acetate. The organic layerwas washed with saturated brine, dried over anhydrous magnesium sulfate,and concentrated under reduced pressure. The obtained extract wasdissolved in N,N-dimethylformamide (50 mL), N-methoxymethanaminehydrochloride (1.4 g), 1-hydroxybenzotriazole (2.3 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.8 g) andtriethylamine (2.1 mL) were added, and the mixture was stirred at roomtemperature for 16 hr. The reaction mixture was diluted with ethylacetate, washed with 1 N hydrochloric acid and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The residue obtained by purificationby silica gel column chromatography was dissolved in tetrahydrofuran (20mL), and methylmagnesium bromide (1.0 M tetrahydrofuran solution, 8.1mL) was added at room temperature. The reaction mixture was stirred for3 hr, saturated aqueous ammonium chloride solution was added, and themixture was extracted with ethyl acetate. The obtained ethyl acetatelayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The obtained residue was purified by silica gel column chromatography togive the title compound as a colorless solid (1.3 g, 28%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.3 Hz, 3H) 1.51-1.72 (m, 2H)2.16 (s, 3H) 2.41-2.49 (m, 2H) 2.91-3.00 (m, 2H) 3.15-3.31 (m, 2H)3.39-3.51 (m, 1H) 3.99 (s, 2H) 5.34-5.54 (m, 1H) 7.37-7.62 (m, 6H)7.74-7.81 (m, 1H) 7.93 (dd, J=7.7, 0.9 Hz, 1H) 8.23 (s, 1H)

Reference Example 2634′-{[4-(cis-3-acetylcyclobutyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of propyl3-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclobutanecarboxylate(5 g), 1N aqueous sodium hydroxide solution (10 mL), methanol (10 mL)and tetrahydrofuran (10 mL) was stirred at room temperature for 2 hr.The reaction mixture was adjusted to pH 4 with water and 1 Nhydrochloric acid and extracted with ethyl acetate. The organic layerwas washed with saturated brine, dried over anhydrous magnesium sulfate,and concentrated under reduced pressure. The obtained extract wasdissolved in N,N-dimethylformamide (50 mL), N-methoxymethanaminehydrochloride (1.4 g), 1-hydroxybenzotriazole (2.3 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.8 g) andtriethylamine (2.1 mL) were added, and the mixture was stirred at roomtemperature for 16 hr. The reaction mixture was diluted with ethylacetate, washed with 1 N hydrochloric acid and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The residue obtained by purificationby silica gel column chromatography was dissolved in tetrahydrofuran (20mL), and methylmagnesium bromide (1.0 M tetrahydrofuran solution, 6.1mL) was added at room temperature. The reaction mixture was stirred for3 hr, saturated aqueous ammonium chloride solution was added, and themixture was extracted with ethyl acetate. The obtained ethyl acetatelayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The obtained residue was purified by silica gel column chromatography togive the title compound as a colorless solid (2.2 g, 49%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.3 Hz, 3H) 1.49-1.69 (m, 2H)2.11 (s, 3H) 2.40-2.49 (m, 2H) 2.89-3.23 (m, 5H) 3.98 (s, 2H) 5.28-5.43(m, 1H) 7.37-7.63 (m, 6H) 7.72-7.82 (m, 1H) 7.93 (dd, J=7.7, 0.9 Hz, 1H)8.19 (s, 1H)

Reference Example 2644′-{[4-(trans-3-hydroxycyclobutyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

To a mixture of4′-{[4-(trans-3-acetylcyclobutyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(1.3 g), 30% hydrogen peroxide water (3.5 g) and chloroform (20 mL) wasgradually added trifluoroacetic acid anhydride (7.7 mL) at roomtemperature, and the reaction mixture was warmed to 60° C. and stirredfor 24 hr. Saturated aqueous sodium hydrogen carbonate and sodiumthiosulfate were added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The obtained residue wasdissolved in tetrahydrofuran (10 mL) and methanol (10 mL), 1N aqueoussodium hydroxide solution (5 mL) was added, and the mixture was stirredat room temperature for 30 min. 1N Aqueous hydrochloric acid solutionwas added to the reaction mixture, and the mixture was extracted withethyl acetate. The ethyl acetate layer was washed with saturated brine,and dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography to give the title compound as a colorless solid(0.28 g, 23%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.2 Hz, 3H) 1.51-1.67 (m, 2H)2.11-2.24 (m, 2H) 2.92-3.01 (m, 2H) 3.15-3.28 (m, 2H) 3.99 (s, 2H)4.42-4.54 (m, 1H) 5.12 (d, J=4.9 Hz, 1H) 5.78 (t, J=8.7 Hz, 1H)7.37-7.63 (m, 6H) 7.73-7.81 (m, 1H) 7.93 (d, J=7.6 Hz, 1H) 8.21 (s, 1H)

Reference Example 2654′-{[4-(cis-3-hydroxycyclobutyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

To a mixture of4′-{[4-(cis-3-acetylcyclobutyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(2.2 g), 30% hydrogen peroxide water (5.9 g) and chloroform (30 mL) wasgradually added trifluoroacetic acid anhydride (13 mL) at roomtemperature, and the reaction mixture was warmed to 60° C. and stirredfor 24 hr. Saturated aqueous sodium hydrogen carbonate and sodiumthiosulfate were added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The obtained residue wasdissolved in tetrahydrofuran (10 mL) and methanol (10 mL), 1N aqueoussodium hydroxide solution (5 mL) was added, and the mixture was stirredat room temperature for 30 min. 1N Aqueous hydrochloric acid solutionwas added to the reaction mixture, and the mixture was extracted withethyl acetate. The obtained ethyl acetate layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography to give the title compound as acolorless solid (0.58 g, 27%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.3 Hz, 3H) 1.51-1.68 (m, 2H)2.11-2.23 (m, 2H) 2.91-3.02 (m, 2H) 3.17-3.29 (m, 2H) 3.99 (s, 2H) 4.49(t, J=6.6 Hz, 1H) 5.12 (br.s., 1H) 5.70-5.86 (m, 1H) 7.37-7.62 (m, 6H),7.74-7.81 (m, 1H), 7.92 (d, J=1.1 Hz, 1H) 8.21 (s, 1H)

Reference Example 266 ethyl[(cis-3-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclobutyl)oxy]acetate

To a mixture of4′-{[4-(cis-3-hydroxycyclobutyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.3 g), rhodium(I) acetate (0.003 g) and toluene (20 mL) was addeddropwise ethyl diazoacetate (0.66 mL) at 80° C., and the mixture wasstirred at the same temperature for 1 hr. The reaction mixture wasconcentrated under reduced pressure, and the obtained residue wassubjected to silica gel column chromatography to give the title compoundas a colorless solid (0.2 g, 57%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89-0.99 (m, 3H) 1.14-1.25 (m, 3H)1.52-1.68 (m, 2H) 2.56-2.66 (m, 2H) 2.91-3.19 (m, 4H) 3.85-4.19 (m, 7H)4.88-5.05 (m, 1H) 7.38-7.62 (m, 4H) 7.73-7.82 (m, 1H) 7.93 (d, J=7.6 Hz,1H) 8.22 (s, 1H)

Reference Example 2674′-({4-[cis-3-(2-hydroxy-2-methylpropoxy)cyclobutyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

Ethyl[(cis-3-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclobutyl)oxy]acetate(0.2 g) was dissolved in tetrahydrofuran (10 mL), and methylmagnesiumbromide (1.0 M tetrahydrofuran solution, 1.2 mL) was added at roomtemperature. The reaction mixture was stirred for 6 hr, saturatedaqueous ammonium chloride solution was added, and the mixture wasextracted with ethyl acetate. The obtained ethyl acetate layer waswashed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The obtained residuewas purified by silica gel column chromatography to give the titlecompound as a colorless solid (0.15 g, 78%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.3 Hz, 3H) 1.09 (s, 6H)1.53-1.68 (m, 2H) 2.54-2.66 (m, 2H) 2.91-3.08 (m, 4H) 3.11 (s, 2H)3.76-3.88 (m, 1H) 3.99 (s, 2H) 4.31 (s, 1H) 4.85-4.99 (m, 1H) 7.38-7.63(m, 6H), 7.73-7.82 (m, 1H) 7.93 (dd, J=7.8, 0.8 Hz, 1H) 8.21 (s, 1H)

Reference Example 268 ethyl[(trans-3-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclobutyl)oxy]acetate

To a mixture of4′-{[4-(trans-3-hydroxycyclobutyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.28 g), rhodium(I) acetate (0.0028 g) and toluene (10 mL) was addeddropwise ethyl diazoacetate (0.62 mL) at 80° C., and the mixture wasstirred at the same temperature for 1 hr. The reaction mixture wasconcentrated, and the obtained residue was subjected to silica gelcolumn chromatography to give the title compound as a colorless solid(0.056 g, 17%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.05 (t, J=7.3 Hz, 3H) 1.26-1.33 (m,3H) 1.65-1.78 (m, 2H) 2.49-2.61 (m, 2H) 2.97-3.06 (m, 2H) 3.21-3.36 (m,2H) 4.02 (s, 2H) 4.05 (s, 2H) 4.19-4.28 (m, 2H) 4.52-4.64 (m, 1H)5.82-5.99 (m, 1H) 7.33-7.51 (m, 6H) 7.58-7.67 (m, 1H) 7.75 (dd, J=7.7,1.3 Hz, 1H) 7.93 (s, 1H)

Reference Example 2694′-({4-[trans-3-(2-hydroxy-2-methylpropoxy)cyclobutyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

Ethyl[(trans-3-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclobutyl)oxy]acetate(0.08 g) was dissolved in tetrahydrofuran (5 mL), and methylmagnesiumbromide (1.0 M tetrahydrofuran solution, 0.46 mL) was added at roomtemperature. The reaction mixture was stirred for 6 hr, saturatedaqueous ammonium chloride solution was added to the reaction mixture,and the mixture was extracted with ethyl acetate. The obtained ethylacetate layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The obtained residue was purified by silica gel column chromatography togive the title compound as a colorless solid (0.056 g, 72%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.2 Hz, 3H) 1.24 (s, 6H)1.66-1.79 (m, 2H) 2.33 (br. s., 1H) 2.40-2.51 (m, 2H) 2.99-3.07 (m, 2H)3.22 (s, 2H) 3.25-3.38 (m, 2H) 4.02 (s, 2H) 4.43 (t, J=6.8 Hz, 1H)5.81-5.95 (m, 1H) 7.34-7.51 (m, 6H), 7.58-7.67 (m, 1H) 7.74 (d, J=8.0Hz, 1H) 7.94 (s, 1H)

Reference Example 2704′-({4-[trans-3-(2-ethyl-2-hydroxybutoxy)cyclobutyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

Ethyl[(trans-3-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclobutyl)oxy]acetate(0.077 g) was dissolved in tetrahydrofuran (10 mL), and ethylmagnesiumbromide (3.0 M diethyl ether solution, 0.15 mL) was added at roomtemperature. The reaction mixture was stirred for 6 hr, saturatedaqueous ammonium chloride solution was added to the reaction mixture,and the mixture was extracted with ethyl acetate. The obtained ethylacetate layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The obtained residue was purified by silica gel column chromatography togive the title compound as a colorless solid (0.06 g, 76%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.89 (t, J=7.5 Hz, 6H) 1.06 (t, J=7.4Hz, 3H) 1.46-1.61 (m, 4H) 1.63-1.79 (m, 2H) 2.40-2.51 (m, 2H) 2.98-3.08(m, 2H) 3.22-3.37 (m, 4H) 4.02 (s, 2H) 4.36-4.45 (m, 1H) 5.78-5.94 (m,1H) 7.34-7.51 (m, 6H), 7.59-7.67 (m, 1H) 7.75 (dd, J=7.8, 1.0 Hz, 1H)7.94 (s, 1H)

Reference Example 2714′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-{(4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(27.7 g) in tetrahydrofuran (200 mL) was added 3M hydrochloric acid (200mL), and the mixture was stirred at 60° C. for 15 hr. The mixture wasallowed to cool to room temperature, diluted with ethyl acetate, andneutralized with 8M aqueous sodium hydroxide solution. The mixture wasextracted with ethyl acetate, and the organic layer was successivelywashed with water and brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was crystallized using ethyl acetate, and theresulting solid was collected by filtration, and dissolved intetrahydrofuran (100 mL). This solution was added dropwise to a solutionof lithium borohydride (2M tetrahydrofuran solution, 37 mL) intetrahydrofuran (150 mL) at −5° C. over 30 min. After stirring for 1.5hr, ethyl acetate and saturated aqueous ammonium chloride solution wereadded. The mixture was extracted with ethyl acetate, and the organiclayer was successively washed with water and brine, dried over anhydrousmagnesium sulfate, and concentrated. The residue was purified by silicagel column chromatography to give the title compound as a pale-yellowamorphous solid (21.1 g, 84%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.3 Hz, 3H), 1.41-1.62 (m,3H), 1.63-1.89 (m, 4H), 2.08-2.19 (m, 2H), 2.36-2.58 (m, 2H), 3.00-3.12(m, 2H), 3.67-3.84 (m, 1H), 4.01 (s, 2H), 4.76 (br. s., 1H), 5.99 (d,J=2.1 Hz, 1H), 7.33-7.78 (m, 9H)

Reference Example 2722-(5-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}thiophen-2-yl)benzonitrile

A mixture of2-(5-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}thiophen-2-yl)benzonitrile(0.69 g), 3N hydrochloric acid (20 mL) and tetrahydrofuran (20 mL) wasstirred at 70° C. for 16 hr. The reaction mixture was diluted with ethylacetate, washed with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure. The obtainedresidue was dissolved in tetrahydrofuran (5 mL) and methanol (5 mL),sodium borohydride (0.076 g) was added, and the mixture was stirred atroom temperature for 1 hr. After evaporation of the solvent underreduced pressure, the residue was extracted with water and ethylacetate. The obtained ethyl acetate layer was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.41 g, 63%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.11 (t, J=7.4 Hz, 3H) 1.44-1.57 (m,2H) 1.73-1.86 (m, 4H) 2.07-2.18 (m, 2H) 2.65-2.82 (m, 2H) 3.01-3.11 (m,2H) 3.75-3.90 (m, 1H) 4.13 (s, 2H) 4.99-5.14 (m, 1H) 6.95 (d, J=3.8 Hz,1H) 7.30-7.39 (m, 1H) 7.47 (d, J=3.6 Hz, 1H) 7.55 (d, J=4.0 Hz, 2H) 7.70(d, J=7.7 Hz, 1H) 7.91 (s, 1H)

Reference Example 273 ethyl({trans-4-[6-{[5-(2-cyanophenyl)thiophen-2-yl]methyl}-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl]cyclohexyl}oxy)acetate

To a mixture of2-(5-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}thiophen-2-yl)benzonitrile(0.4 g), rhodium(I) acetate (0.0019 g) and toluene (10 mL) was addeddropwise ethyl diazoacetate (0.46 mL) at 80° C., and the mixture wasstirred at the same temperature for 1 hr. The reaction mixture wasconcentrated, and the obtained residue was subjected to silica gelcolumn chromatography to give the title compound as a colorless solid(0.25 g, 53%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.11 (t, J=7.3 Hz, 3H) 1.27-1.34 (m,3H) 1.44-1.58 (m, 2H) 1.74-1.86 (m, 4H) 2.17-2.29 (m, 2H) 2.60-2.78 (m,2H) 3.01-3.10 (m, 2H) 3.45-3.57 (m, 1H) 4.13 (s, 4H) 4.19-4.29 (m, 2H)4.99-5.13 (m, 1H) 6.95 (d, J=3.8 Hz, 1H) 7.30-7.38 (m, 1H) 7.47 (d,J=3.8 Hz, 1H) 7.53-7.57 (m, 2H) 7.70 (d, J=7.7 Hz, 1H) 7.90 (s, 1H)

Reference Example 2742-[5-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)thiophen-2-yl]benzonitrile

Ethyl({trans-4-[6-{[5-(2-cyanophenyl)thiophen-2-yl]methyl}-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl]cyclohexyl}oxy)acetate(0.25 g) was dissolved in tetrahydrofuran (10 mL), and methylmagnesiumbromide (1.0 M tetrahydrofuran solution, 0.44 mL) was added at roomtemperature. The reaction mixture was stirred at 70° C. for 6 hr,saturated aqueous ammonium chloride solution was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The obtainedethyl acetate layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.12 g,49%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.11 (t, J=7.4 Hz, 3H) 1.21 (s, 6H)1.39-1.54 (m, 2H) 1.74-1.87 (m, 4H) 2.13-2.24 (m, 2H) 2.60-2.79 (m, 2H)3.02-3.10 (m, 2H) 3.31 (s, 2H) 3.39-3.51 (m, 1H) 4.12 (q, J=7.2 Hz, 2H)5.01-5.16 (m, 1H) 6.95 (d, J=3.8 Hz, 1H) 7.30-7.39 (m, 1H) 7.47 (d,J=3.8 Hz, 1H) 7.55 (d, J=3.8 Hz, 2H) 7.70 (d, J=8.0 Hz, 1H) 7.91 (s, 1H)

Reference Example 2754′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)-2′-methylbiphenyl-2-carbonitrile

Ethyl[(trans-4-{6-[(2′-cyano-2-methylbiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate(0.71 g) was dissolved in tetrahydrofuran (10 mL), and methylmagnesiumbromide (1.4 M tetrahydrofuran solution, 2.7 mL) was added at 0° C. Thereaction mixture was stirred for 30 min, 1 N hydrochloric acid wasadded, and the mixture was extracted with ethyl acetate. The obtainedethyl acetate layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography to give the title compound as a colorless oil (0.41 g,59%).

¹H NMR (300 MHz, CDCl₃) δ 1.04 (t, J=7.2, 3H), 1.20 (s, 6H), 1.36-2.30(m, 12H), 2.43 (s, 3H), 2.64-3.06 (m, 4H), 3.31 (s, 2H), 3.38-3.52 (m,1H), 3.94 (s, 2H), 4.94-5.08 (m, 1H), 7.06-7.17 (m, 3H), 7.30-7.46 (m,2H), 7.56-7.64 (m, 1H), 7.68-7.74 (m, 1H)

Reference Example 2762-(5-{[4-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}pyridin-2-yl)benzonitrile

A mixture of ethyl2-{[6-(2-cyanophenyl)pyridin-3-yl]methyl}-3-oxohexanoate (1.8 g),N-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-4H-1,2,4-triazol-3-amine(1.4 g) and N,N-diethylaniline (30 mL) was stirred at 180° C. for 8 hr.The obtained reaction mixture was diluted with ethyl acetate, washed 3times with 1 N hydrochloric acid and saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.42 g,21%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.05 (s, 6H) 0.79-1.00 (m, 12H) 1.35-2.68(m, 10H) 2.91-3.06 (m, 2H) 3.57-3.77 (m, 0H) 4.02 (s, 2H) 4.77-4.97 (m,1H) 7.56-7.67 (m, 1H) 7.71-7.99 (m, 4H) 8.10-8.23 (m, 1H) 8.64-8.71 (m,1H)

Reference Example 277 ethyl({trans-4-[6-{[6-(2-cyanophenyl)pyridin-3-yl]methyl}-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl]cyclohexyl}oxy)acetate

A mixture of2-(5-{[4-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}pyridin-2-yl)benzonitrile(0.42 g), tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 1.1mL) and tetrahydrofuran (20 mL) was stirred at 70° C. for 16 hr. Ethylacetate and water were added to the reaction mixture, and the mixturewas extracted with ethyl acetate. The organic layer was washed withwater and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure. The obtainedresidue was dissolved in acetonitrile (20 mL),1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.31 g) wasadded, and the mixture was stirred at room temperature for 3 hr.Saturated aqueous sodium hydrogen carbonate solution and sodiumthiosulfate were added to the reaction mixture, and the mixture wasstirred at room temperature for 2 hr, and extracted with ethyl acetate.The organic layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The obtained residue was dissolved in tetrahydrofuran (3 mL)and methanol (3 mL), sodium borohydride (0.016 g) was added, and themixture was stirred at room temperature for 1 hr. After evaporation ofthe solvent under reduced pressure, the residue was extracted with waterand ethyl acetate. The obtained ethyl acetate layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. To a solution (10 mL) of theobtained residue in toluene was added dropwise ethyl diazoacetate (0.14mL) in the presence of rhodium(I) acetate (0.0012 g) at 80° C., and themixture was stirred at the same temperature for 1 hr. The reactionmixture was concentrated, and the obtained residue was subjected tosilica gel column chromatography to give the title compound as acolorless solid (0.06 g, 15%).

¹H NMR (300 MHz, DMSO-d₆) δ 1.09 (t, J=7.3 Hz, 3H) 1.30 (t, J=7.1 Hz,3H) 1.46-1.86 (m, 6H) 2.18-2.27 (m, 2H) 2.60-2.76 (m, 2H) 3.01-3.09 (m,2H) 3.43-3.58 (m, 1H) 4.00 (s, 2H) 4.13 (s, 2H) 4.23 (q, J=7.2 Hz, 2H)4.97-5.13 (m, 1H) 7.49 (t, J=7.5 Hz, 1H) 7.64-7.84 (m, 5H) 7.92 (s, 1 H)8.68 (s, 1H)

Reference Example 2784′-{[4-butyl-2-(methylsulfanyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-6-oxo-2-sulfanyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(3.6 g), methyl iodide (0.83 mL), potassium hydroxide (0.68 g) andmethanol (30 mL) was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (3.5 g,95%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.79-0.87 (m, 3H) 1.19-1.34 (m, 2H)1.41-1.56 (m, 2H) 2.46-2.57 (m, 5H) 3.84 (s, 2H) 7.32 (q, J=8.3 Hz, 2H)7.44-7.51 (m, 2H) 7.52-7.61 (m, 2H) 7.72-7.81 (m, 1H) 7.89-8.00 (m, 1H)12.7 (br. s., 1H)

Reference Example 2794′-[(4-butyl-2-hydrazino-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile

A mixture of4′-{[4-butyl-2-(methylsulfanyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(3.5 g), hydrazine hydrate (10 mL) and n-butanol (100 mL) was stirred at120° C. for 6 hr. The reaction mixture was cooled to room temperature,and the precipitated solid was collected by filtration. The obtainedsolid was washed with methanol to give the title compound as a colorlesssolid (2.6 g, 77%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.81 (t, J=7.2 Hz, 3H) 1.16-1.33 (m, 2H)1.33-1.51 (m, 2H) 2.36 (t, J=7.4 Hz, 2H) 3.76 (s, 2H) 7.31 (q, J=8.3 Hz,2H) 7.41-7.50 (m, 2H) 7.51-7.64 (m, 2H) 7.72-7.83 (m, 1H) 7.92 (d, J=8.0Hz, 1H) 8.25 (br. s., 1H)

Reference Example 2804′-[(5-butyl-7-oxo-7,8-dihydro[1,2,4]triazolo[4,3-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-hydrazino-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(2.6 g) and triethyl orthoformate (30 mL) was stirred at 100° C. for 16hr. The reaction mixture was concentrated, and ethyl acetate and waterwere added to the obtained residue. The ethyl acetate layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.46 g, 17%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.82 (t, J=7.3 Hz, 3H) 1.23-1.39 (m, 2H)1.41-1.58 (m, 2H) 2.58-2.67 (m, 2H) 3.96 (s, 2 H) 7.33-7.41 (m, 2H)7.43-7.51 (m, 2H) 7.52-7.62 (m, 2H) 7.71-7.81 (m, 1H) 7.92 (dd, J=7.8,0.85 Hz, 1H) 9.01 (s., 1H), 13.5 (br. s., 1H)

Reference Example 2814′-{[5-butyl-8-[4-(1-methylethoxyphenyl)-7-oxo-7,8-dihydro[1,2,4]triazolo[4,3-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

To a suspension (15 mL) of4′-[(5-butyl-7-oxo-7,8-dihydro[1,2,4]triazolo[4,3-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.43 g), [4-(1-methylethoxy)phenyl]boronic acid (0.4 g), triethylamine(0.5 mL), pyridine (1 mL) and molecular sieves 4A (1 g) indichloromethane was added copper(II) acetate (0.41 g), and the mixturewas stirred for 16 hr. The reaction mixture was diluted with ethylacetate, the insoluble material was filtered off through celite, and thefiltrate was concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.33 g,56%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.00 (t, J=7.2 Hz, 3H) 1.32-1.41 (m,6H) 1.46-1.58 (m, 2H) 1.58-1.72 (m, 2H) 2.91-3.01 (m, 2H) 4.04 (s, 2H)4.51-4.63 (m, 1H) 7.02 (d, J=8.7 Hz, 2H) 7.30-7.44 (m, 5H) 7.44-7.52 (m,3H) 7.59-7.68 (m, 1H) 7.75 (d, J=7.6 Hz, 1H) 8.36 (s, 1H)

Reference Example 2823-methyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine hydrochloride

To a solution (20 mL) of 1-benzyl-3-methyl-1H-pyrazol-5-amine (1 g) andtetrahydro-4H-pyran-4-one (0.8 g) in acetic acid was added sodiumcyanoborohydride (1.7 g), and the mixture was stirred at roomtemperature for 16 hr. Water was added to the reaction mixture, and thesolvent was evaporated under reduced pressure. The obtained residue waspoured into saturated aqueous sodium hydrogen carbonate, and the mixturewas extracted with a mixed solvent of ethyl acetate and isopropylalcohol (3:1). The obtained extract was dried over anhydrous sodiumsulfate, and the solvent was evaporated under reduced pressure. Theobtained residue was dissolved in methanol (30 mL) and acetic acid (30mL), activated carbon-supported 20 mass % palladium hydroxide (1 g) wasadded, and the mixture was stirred at room temperature for 4 days underhydrogen stream. The insoluble material was filtered through celite, andthe filtrate was concentrated. The obtained residue was dissolved inethyl acetate (20 mL), and 4N hydrochloric acid-ethyl acetate (1.8 mL)was added at room temperature. The precipitated solid was collected byfiltration to give the title compound as a colorless solid (0.71 g,61%).

¹H NMR (300 MHz, DMSO-d₆) δ 1.34-1.51 (m, 2H) 1.76-1.89 (m, 2H) 2.21 (s,3H) 3.28-3.41 (m, 2H) 3.41-3.55 (m, 1H) 3.78-3.93 (m, 2H) 5.62 (s, 1H)7.39 (br. s., 1H) 13.87 (br. s., 1H)

Reference Example 2834′-{[2-methyl-5-oxo-7-propyl-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate(0.96 g), 3-methyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-aminehydrochloride (0.3 g) and N,N-diethylaniline (10 mL) was stirred at 180°C. for 2 hr. The obtained reaction mixture was diluted with ethylacetate, washed 3 times with 1 N hydrochloric acid and saturated brine,and dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography to give the title compound as a colorless solid(0.27 g, 42%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.05 (t, J=7.3 Hz, 3H) 1.59-1.79 (m,4H) 2.35 (s, 3H) 2.51-2.69 (m, 2H) 2.96-3.08 (m, 2H) 3.48-3.60 (m, 2H)4.00 (s, 2H) 4.07-4.18 (m, 2H) 5.26-5.41 (m, 1H) 5.95 (s, 1H) 7.33-7.52(m, 6H) 7.56-7.66 (m, 1H) 7.74 (dd, J=7.8, 1.0 Hz, 1H)

Reference Example 284 tert-butyl[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate

To a suspension of4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(21.1 g) and tetrabutylammonium hydrogen sulfate (1.5 g) in toluene (160mL)-50% sodium hydroxide (160 mL) was added dropwise tert-butylbromoacetate (20 mL) at 50° C., and the mixture was stirred at 50° C.for 1.5 hr. The mixture was allowed to cool to room temperature, dilutedwith ethyl acetate and then neutralized with 6M hydrochloric acid. Themixture was extracted with ethyl acetate, and the organic layer waswashed with water and brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as an amorphous pale-yellowsolid (24.4 g, 93%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.2 Hz, 3H), 1.28-1.73 (m, 15H),2.04-2.46 (m, 4H), 2.92-3.02 (m, 2H), 3.37-3.52 (m, 1H), 3.97 (s, 2H),4.00 (s, 2H), 4.62 (br. s., 1H), 6.42 (d, J=1.1 Hz, 1H), 7.34-7.97 (m,9H)

Reference Example 2854′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of tert-butyl[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate(38.0 g) in tetrahydrofuran (200 mL) was added dropwise methylmagnesiumbromide (1 M tetrahydrofuran solution, 200 mL) at 0° C., and the mixturewas stirred for 2 hr. The mixture was diluted with ethyl acetate, andthen saturated aqueous ammonium chloride solution was added. The mixturewas extracted with ethyl acetate, washed with brine, dried overanhydrous magnesium sulfate, and concentrated. The residue was purifiedby silica gel column chromatography to give the title compound as apale-yellow amorphous solid (32.1 g, 91%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.05 (t, J=7.4 Hz, 3H), 1.21 (s, 6H),1.36-1.90 (m, 7H), 2.13-2.54 (m, 4H), 3.01-3.10 (m, 2H), 3.31 (s, 2H),3.32-3.44 (m, 1H), 4.01 (s, 2H), 4.74 (br. s., 1H), 5.98 (d, J=2.3 Hz,1H), 7.33-7.78 (m, 9H)

Reference Example 2864′-{[3-methyl-5-oxo-7-propyl-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (1.5g), 4-methyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine (0.4 g),1,8-diazabicyclo[5.4.0]undec-7-ene (0.3 mL) and N,N-diethylaniline (10mL) was stirred at 180° C. for 16 hr. The obtained reaction mixture wasdiluted with ethyl acetate, washed 3 times with 1 N hydrochloric acidand saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.63 g, 61%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.03 (t, J=7.3 Hz, 3H) 1.62-1.76 (m,4H) 2.35 (s, 3H) 2.96-3.16 (m, 4H) 3.38-3.52 (m, 2H) 3.98 (s, 2H)4.07-4.18 (m, 2H) 4.44-4.58 (m, 1H) 7.32-7.53 (m, 7H) 7.57-7.65 (m, 1H)7.74 (dd, J=7.7, 0.9 Hz, 1H)

Reference Example 287 ethyl2-[(2′-cyano-2-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate

To a suspension (200 mL) of 60% sodium hydride (1.8 g) intetrahydrofuran was added dropwise a solution (50 mL) of ethyl3-oxohexanoate (10.9 g) in tetrahydrofuran at 0° C. The mixture wasstirred at the same temperature for 30 min,4′-(bromomethyl)-2′-fluorobiphenyl-2-carbonitrile (10.0 g) was added,and the mixture was stirred at room temperature for 16 hr. The reactionmixture was poured into 1 N hydrochloric acid, and the mixture wasextracted with ethyl acetate. The obtained ethyl acetate layer waswashed with saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow oil (12.9 g,100%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.80 (t, J=7.4 Hz, 3H) 1.11 (t, J=7.1 Hz,3H) 1.39-1.54 (m, 2H) 2.41-2.64 (m, 2H) 3.04-3.21 (m, 2H) 4.08 (q, J=7.7Hz, 2H) 7.18-7.32 (m, 2H) 7.41 (t, J=7.9 Hz, 1H) 7.54-7.67 (m, 2H) 7.81(t, J=7.1 Hz, 1H) 7.97 (dd, J=7.8, 0.8 Hz, 1H)

Reference Example 2884′-{[4-(cis-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

Sodium tetrahydroborate (0.55 g) was dissolved in methanol (30 mL), amixture of4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(5.9 g) and methanol (30 mL) was added dropwise at 0° C., andtetrahydrofuran (10 mL) was added. The mixture was stirred at roomtemperature for 1.5 hr, sodium tetrahydroborate (0.23 g) was added, andthe mixture was stirred at room temperature for 30 min. Saturatedaqueous ammonium chloride solution was added to the reaction mixture.The solvent was evaporated under reduced pressure, and the residue wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.29 g, 13%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.07 (t, J=7.35 Hz, 3H) 1.54-1.80 (m,6H) 1.90-2.02 (m, 2H) 2.88-3.11 (m, 4H) 4.03 (s, 2H) 4.06-4.20 (m, 1H)5.01-5.21 (m, 1H) 7.33-7.53 (m, 6H) 7.57-7.68 (m, 1H) 7.75 (dd, J=7.72,0.94 Hz, 1H) 7.94 (s, 1H)

Reference Example 2894′-({4-[trans-4-(4-{[tert-butyl(dimethyl)silyl]oxy}phenoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

4′-{[4-(cis-4-Hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.46 g), 4-{[tert-butyl(dimethyl)silyl]oxy}phenol (0.49 g) andtriphenylphosphine (0.29 g) were dissolved in tetrahydrofuran (2 mL), asolution of diisopropyl azodicarboxylate (0.58 mL, 1.9 M toluenesolution) in tetrahydrofuran (1 mL) was added dropwise at 0° C., and themixture was stirred at room temperature for 45 hr. The reaction mixturewas added to 1 M hydrochloric acid, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as an oily compound (0.22 g,33%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.16 (s, 6H) 0.98 (s, 9H) 1.07 (t,J=7.38 Hz, 3H) 1.61-1.90 (m, 6H) 2.18-2.33 (m, 2H) 2.68-2.93 (m, 2H)2.97-3.09 (m, 2H) 3.99-4.06 (m, 2H) 4.17-4.31 (m, 1H) 5.03-5.23 (m, 1H)6.65-6.87 (m, 4H) 7.32-7.51 (m, 6H) 7.58-7.66 (m, 1H) 7.74 (d, J=7.95Hz, 1H) 7.90-7.94 (m, 1H)

Reference Example 2904′-({4-[cis-4-(4-{[tert-butyl(dimethyl)silyl]oxy}phenoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

4′-{[4-(trans-4-Hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.46 g), 4-{[tert-butyl(dimethyl)silyl]oxy}phenol (0.49 g) andtriphenylphosphine (0.29 g) were dissolved in tetrahydrofuran (2 mL), asolution of diisopropyl azodicarboxylate (0.58 mL, 1.9 M toluenesolution) in tetrahydrofuran (1 mL) was added dropwise at 0° C., and themixture was stirred at room temperature for 45 hr. The reaction mixturewas added to 1 M hydrochloric acid, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as an oily compound (0.31 g,47%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.16 (s, 6H) 0.98 (s, 9H) 1.06 (t,J=7.38 Hz, 3H) 1.59-1.86 (m, 6H) 2.12-2.33 (m, 2H) 2.88-3.24 (m, 4H)4.03 (s, 2H) 4.41-4.50 (m, 1H) 4.98-5.22 (m, 1H) 6.67-6.81 (m, 2H)6.86-6.98 (m, 2H) 7.34-7.54 (m, 6H) 7.57-7.67 (m, 1H) 7.74 (d, J=7.57Hz, 1H) 7.96 (s, 1H)

Reference Example 2914′-{[4-(cis-4-hydroxy-4-methylcyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

To a mixture of4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(1.8 g) and diethyl ether (15 mL) was added dropwise methylmagnesiumbromide (2.0 mL, 3.0 M diethyl ether solution) at 0° C., and the mixturewas stirred at room temperature for 4 hr. Tetrahydrofuran (15 mL) wasadded, methylmagnesium bromide (4.0 mL, 1.0 M tetrahydrofuran solution)was added dropwise, and the mixture was stirred at 40° C. for 24 hr. Thereaction mixture was added to 1 M hydrochloric acid, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.41 g, 21%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.35 Hz, 3H) 1.29 (s, 3H)1.58-1.97 (m, 8H) 2.82-3.10 (m, 4H) 4.02 (s, 2H) 4.98-5.16 (m, 1H)7.32-7.53 (m, 6H) 7.58-7.68 (m, 1H) 7.71-7.78 (m, 1H) 7.94 (s, 1H)

Reference Example 2924′-{[4-(trans-4-hydroxy-4-methylcyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

To a mixture of4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(1.8 g) and diethyl ether (15 mL) was added dropwise methylmagnesiumbromide (2.0 mL, 3.0 M diethyl ether solution) at 0° C., and the mixturewas stirred at room temperature for 4 hr. Tetrahydrofuran (15 mL) wasadded, methylmagnesium bromide (4.0 mL, 1.0 M tetrahydrofuran solution)was added dropwise, and the mixture was stirred at 40° C. for 24 hr. Thereaction mixture was added to 1 M hydrochloric acid, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.35 g, 18%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.35 Hz, 3H) 1.39 (s, 1H)1.48 (s, 3H) 1.58-1.98 (m, 8H) 2.67-2.94 (m, 2H) 2.96-3.09 (m, 2H) 4.02(s, 2H) 4.98-5.18 (m, 1H) 7.31-7.52 (m, 6H) 7.58-7.69 (m, 1H) 7.71-7.79(m, 1H) 7.92 (s, 1H)

Reference Example 2934′-({4-[cis-4-(4-acetylphenoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

4′-{[4-(trans-4-Hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(4.6 g), 4-bromophenol (3.4 g) and triphenylphosphine (5.2 g) weredissolved in tetrahydrofuran (5 mL), a solution of diisopropylazodicarboxylate (10 mL, 1.9 M toluene solution) in tetrahydrofuran (5mL) was added dropwise, and the mixture was stirred at room temperaturefor 18 hr. The reaction mixture was added to 1 M hydrochloric acid, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue obtainedby purification by silica gel column chromatography was mixed withdibutyl(1-ethoxyethenyl)pentylstannane (4.0 mL),dichlorobis(triphenylphosphine)palladium (0.35 g) and tetrahydrofuran(30 mL), and the mixture was heated under reflux for 64 hr. Aqueouspotassium fluoride solution was added, and the obtained mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (1.8 g, 32%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.19 Hz, 3H) 1.60-1.85 (m,6H) 2.17-2.32 (m, 2H) 2.56 (s, 3H) 2.95-3.20 (m, 4H) 4.03 (s, 2H)4.66-4.77 (m, 1H) 5.05-5.23 (m, 1H) 7.07 (d, J=9.09 Hz, 2H) 7.33-7.53(m, 6H) 7.58-7.67 (m, 1H) 7.74 (d, J=7.57 Hz, 1H) 7.91-7.99 (m, 3H)

Reference Example 2944′-({4-[trans-4-(4-bromophenoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

4′-{[4-(cis-4-Hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(1.2 g), 4-bromophenol (0.93 g) and triphenylphosphine (1.4 g) weredissolved in tetrahydrofuran (1.5 mL), a solution of diisopropylazodicarboxylate (2.8 mL, 1.9 M toluene solution) in tetrahydrofuran(2.0 mL) was added dropwise, and the mixture was stirred at roomtemperature for 18 hr. The reaction mixture was added to 1 Mhydrochloric acid, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.67 g, 40%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.07 (t, J=7.38 Hz, 3H) 1.59-1.94 (m,6H) 2.18-2.39 (m, 2H) 2.70-2.90 (m, 2H) 2.96-3.10 (m, 2H) 4.02 (s, 2H)4.23-4.39 (m, 1H) 5.02-5.21 (m, 1H) 6.81 (d, J=9.09 Hz, 2H) 7.32-7.53(m, 8H) 7.58-7.68 (m, 1H) 7.75 (d, J=7.95 Hz, 1H) 7.93 (s, 1H)

Reference Example 2954′-({4-[trans-4-(4-acetylphenoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-({4-[trans-4-(4-bromophenoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.67 g), dibutyl(1-ethoxyethenyl)pentylstannane (0.45 mL),dichlorobis(triphenylphosphine)palladium (0.038 g) and tetrahydrofuran(3 mL) was heated under reflux for 64 hr. Aqueous potassium fluoridesolution was added, and the obtained mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.39 g,62%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.07 (t, J=7.35 Hz, 3H) 1.63-1.96 (m,6H) 2.23-2.38 (m, 2H) 2.55 (s, 3H) 2.74-2.93 (m, 2H) 2.98-3.11 (m, 2H)4.02 (s, 2H) 4.37-4.58 (m, 1H) 5.03-5.22 (m, 1H) 6.95 (d, J=8.67 Hz, 2H)7.32-7.54 (m, 6H) 7.57-7.66 (m, 1H) 7.75 (d, J=7.72 Hz, 1H) 7.86-7.99(m, 3H)

Reference Example 2964′-[(4-{cis-4-[4-(1-hydroxy-1-methylethyl)phenoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

4′-({4-[cis-4-(4-Acetylphenoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.50 g) was dissolved in tetrahydrofuran (2 mL), methylmagnesiumbromide (1.8 mL, 1.0 M tetrahydrofuran solution) was added dropwise, andthe mixture was stirred at room temperature for 17 hr. Methylmagnesiumbromide (1.0 mL, 1.0 M tetrahydrofuran solution) was further addeddropwise, and the mixture was stirred at room temperature for 1 hr. Thereaction mixture was added to 1 M hydrochloric acid, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.21 g, 41%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.35 Hz, 3H) 1.58 (s, 6H)1.63-1.81 (m, 6H) 2.16-2.31 (m, 2H) 2.95-3.22 (m, 4H) 4.03 (s, 2H)4.53-4.66 (m, 1H) 5.03-5.24 (m, 1H) 6.95-7.04 (m, 2H) 7.33-7.53 (m, 8H)7.57-7.68 (m, 1H) 7.74 (d, J=7.54 Hz, 1H) 7.96 (s, 1H)

Reference Example 2974′-[(4-{trans-4-[4-(1-hydroxy-1-methylethyl)phenoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

4′-({4-[trans-4-(4-Acetylphenoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.27 g) was dissolved in tetrahydrofuran (1 mL), methylmagnesiumbromide (1.4 mL, 1.0 M tetrahydrofuran solution) was added dropwise, andthe mixture was stirred at room temperature for 16 hr. Methylmagnesiumbromide (0.11 mL, 1.0 M tetrahydrofuran solution) was further addeddropwise, and the mixture was stirred at room temperature for 1 hr. Thereaction mixture was added to 1 M hydrochloric acid, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.17 g, 60%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.07 (t, J=7.38 Hz, 3H) 1.57 (s, 6H)1.59-1.94 (m, 6H) 2.23-2.37 (m, 2H) 2.69-2.89 (m, 2H) 2.96-3.09 (m, 2H)4.02 (s, 2H) 4.28-4.48 (m, 1H) 5.01-5.22 (m, 1H) 6.90 (d, J=8.71 Hz, 2H)7.32-7.54 (m, 8H) 7.57-7.68 (m, 1H) 7.75 (d, J=7.57 Hz, 1H) 7.93 (s, 1H)

Reference Example 2984′-({5-oxo-7-propyl-4-[trans-4-(tetrahydro-2H-pyran-4-ylamino)cyclohexyl]-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

4′-{[5-Oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(2.0 g) and tetrahydro-2H-pyran-4-amine (0.43 g) were dissolved inacetic acid (20 mL) and tetrahydrofuran (8 mL), sodiumtriacetoxyborohydride (1.3 g) was gradually added at room temperature,and the mixture was stirred at room temperature for 24 hr. Water wasadded, and the solvent was evaporated under reduced pressure. Theresidue was gradually added to saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.77 g,32%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.35 Hz, 3H) 1.43-2.00 (m,12H) 2.70-2.85 (m, 3H) 2.96-3.05 (m, 2H) 3.06-3.12 (m, 1H) 3.37-3.49 (m,2H) 3.93-4.06 (m, 4H) 4.99-5.15 (m, 1H) 7.33-7.52 (m, 6H) 7.59-7.66 (m,1H) 7.75 (d, J=7.91 Hz, 1H) 7.91 (s, 1H)

Reference Example 2994′-[(4-{trans-4-[methyl(tetrahydro-2H-pyran-4-yl)amino]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

To a mixture of4′-({5-oxo-7-propyl-4-[trans-4-(tetrahydro-2H-pyran-4-ylamino)cyclohexyl]-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.33 g), sodium sulfate (1.5 g), aqueous formaldehyde solution (0.50mL) and tetrahydrofuran (4 mL) was gradually added sodiumtriacetoxyborohydride (0.63 g) at room temperature, and the mixture wasstirred at room temperature for 114 hr. 0.5M Aqueous sodium hydroxidesolution was added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.13 g,39%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.05 (t, J=7.19 Hz, 3H) 1.40-1.85 (m,10H) 2.10-2.19 (m, 2H) 2.24 (s, 3H) 2.62-2.70 (m, 1H) 2.81-3.07 (m, 5H)3.39 (t, J=11.36 Hz, 2H) 3.98-4.08 (m, 4H) 4.99-5.17 (m, 1H) 7.32-7.52(m, 6H) 7.57-7.68 (m, 1H) 7.74 (d, J=7.95 Hz, 1H) 7.91 (s, 1H)

Reference Example 3004′-{[4-(3-methylidene-1,5-dioxaspiro[5.5]undec-9-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.50 g), 2-methylidenepropane-1,3-diol (0.18 g),4-methylbenzenesulfonic acid (0.020 g) and toluene (20 mL) was heatedwith a Dean-Stark apparatus under reflux for 21 hr. The reaction mixturewas concentrated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.36 g, 64%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.35 Hz, 3H) 1.56-1.79 (m,6H) 2.33-2.44 (m, 2H) 2.82-3.09 (m, 4H) 4.02 (s, 2H) 4.36 (s, 2H) 4.40(s, 2H) 4.87 (br. s., 2H) 5.03-5.18 (m, 1H) 7.33-7.52 (m, 6H) 7.59-7.67(m, 1H) 7.74 (d, J=7.54 Hz, 1H) 7.93 (s, 1H)

Reference Example 3014′-{[4-(3-hydroxy-1,5-dioxaspiro[5.5]undec-9-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

To a mixture of4′-{[4-(3-methylidene-1,5-dioxaspiro[5.5]undec-9-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(2.0 g), sodium periodate (4.1 g), acetone (40 mL), acetonitrile (40 mL)and water (40 mL) was added osmium tetraoxide (1.48 g, 7% immobilizedcatalyst) at 0° C., and the mixture was stirred at room temperature for8 hr. Sodium periodate (1.6 g) and osmium tetraoxide (0.60 g, 7%immobilized catalyst) were added, and the mixture was further stirred atroom temperature for 16 hr. Ethyl acetate and water were added to thereaction mixture, the precipitate was filtered off, and the filtrate wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was dissolved intetrahydrofuran (10 mL) and methanol (20 mL), sodium tetrahydroborate(0.29 g) was added, and the mixture was stirred at room temperature for2 hr. Saturated aqueous sodium hydrogen carbonate solution was added tothe reaction mixture. After evaporation of the solvent under reducedpressure, the residue was extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (1.5 g, 73%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.19 Hz, 3H) 1.38-1.83 (m,6H) 2.09-2.21 (m, 1H) 2.64-3.09 (m, 6H) 3.52-3.63 (m, 1H) 3.73-3.83 (m,1H) 3.85-3.95 (m, 1H) 4.02 (s, 2H) 4.05-4.18 (m, 2H) 5.01-5.21 (m, 1H)7.33-7.52 (m, 6H) 7.58-7.67 (m, 1H) 7.74 (d, J=7.95 Hz, 1H) 7.93 (s, 1H)

Reference Example 3024′-{[4-(3-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dioxaspiro[5.5]undec-9-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

4′-{[4-(3-Hydroxy-1,5-dioxaspiro[5.5]undec-9-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(1.5 g) and 2,6-lutidine (0.50 mL) were dissolved in tetrahydrofuran (5mL), and tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.98 mL)was added at 0° C. The mixture was stirred at room temperature for 1.5hr. Ethyl acetate and water were added to the reaction mixture, themixture was added to 1 M hydrochloric acid, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure to give the title compound as acolorless solid (1.9 g, 100%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.01 (s, 6H) 0.88 (s, 9H) 1.06 (t,J=7.19 Hz, 3H) 1.34-2.03 (m, 8H) 2.68-3.09 (m, 4H) 3.52-3.71 (m, 2H)3.76-3.99 (m, 3H) 4.01 (s, 2H) 5.02-5.18 (m, 1H) 7.33-7.52 (m, 6H)7.58-7.68 (m, 1H) 7.70-7.77 (m, 1H) 7.92 (s, 1H)

Reference Example 3034′-({4-[cis-4-(2-hydroxyethoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(1.0 g), sodium cyanoborohydride (0.32 g), boron trifluoride etherate(0.64 mL) and tetrahydrofuran (20 mL) was heated under reflux for 15 hr.Saturated aqueous sodium hydrogen carbonate solution was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.44 g, 42%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.08 (t, J=7.35 Hz, 3H) 1.49-1.86 (m,6H) 2.05-2.15 (m, 2H) 2.48 (s, 3H) 2.51-2.66 (m, 2H) 2.99-3.09 (m, 2H)3.56-3.63 (m, 2H) 3.65-3.74 (m, 1H) 3.76-3.85 (m, 2H) 4.00 (s, 2H)4.90-5.09 (m, 1H) 7.27-7.34 (m, 2H) 7.41-7.55 (m, 4H) 7.62-7.71 (m, 1H)7.72-7.79 (m, 1H)

Reference Example 3044′-({4-[trans-4-(2-hydroxyethoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(1.0 g), sodium cyanoborohydride (0.32 g), boron trifluoride etherate(0.64 mL) and tetrahydrofuran (20 mL) was heated under reflux for 15 hr.Saturated aqueous sodium hydrogen carbonate solution was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.60 g, 58%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.05 (t, J=7.35 Hz, 3H) 1.36-1.87 (m,6H) 2.01-2.10 (m, 1H) 2.13-2.24 (m, 2H) 2.43 (s, 3H) 2.64-2.83 (m, 2H)2.93-3.03 (m, 2H) 3.39-3.54 (m, 1H) 3.57-3.65 (m, 2H) 3.68-3.77 (m, 2H)3.98 (s, 2H) 4.91-5.09 (m, 1H) 7.30-7.52 (m, 6H) 7.58-7.67 (m, 1H) 7.74(dd, J=7.72, 0.94 Hz, 1H)

Reference Example 3054′-({4-[(3S,6S)-1-oxaspiro[2.5]oct-6-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a mixture of trimethylsulfoxonium iodide (1.1 g) and dimethylsulfoxide (20 mL) was added sodium hydride (0.20 g) at room temperature,and the mixture was stirred at room temperature for 1 hr.4′-{[5-Oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(2.0 g) was added, and the mixture was stirred at room temperature for17 hr. Ethyl acetate and water were added to the reaction mixture, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (1.6 g, 78%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.07 (t, J=7.35 Hz, 3H) 1.36-1.48 (m,2H) 1.66-1.86 (m, 4H) 2.06-2.21 (m, 2H) 2.72 (s, 2H) 2.92-3.19 (m, 4H)4.03 (s, 2H) 5.10-5.27 (m, 1H) 7.35-7.52 (m, 6H) 7.58-7.67 (m, 1H) 7.75(dd, J=7.72, 0.94 Hz, 1H) 7.94 (s, 1H)

Reference Example 3064′-({4-[cis-4-hydroxy-4-(methoxymethyl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-({4-[(3S,6S)-1-oxaspiro[2.5]oct-6-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.40 g), sodium methoxide (0.22 g), methanol (5 mL) and tetrahydrofuran(3 mL) was stirred at room temperature for 22 hr and then at 50° C. for24 hr. After evaporation of the solvent under reduced pressure, waterwas added, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.35 g, 84%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.44 Hz, 3H) 1.43-1.79 (m,6H) 1.83-1.95 (m, 2H) 2.35 (s, 1H) 2.93-3.11 (m, 4H) 3.26 (s, 2H) 3.41(s, 3H) 4.02 (s, 2H) 4.98-5.18 (m, 1H) 7.32-7.53 (m, 6H) 7.58-7.67 (m,1H) 7.71-7.78 (m, 1H) 7.96 (s, 1H)

Reference Example 3074′-({4-[4-(2-hydroxy-2-methylpropoxy)phenyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a mixture of sodium hydride (0.020 g) and N,N-dimethylformamide (2mL) was added4′-{[4-(4-hydroxyphenyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.20 g) at 0° C. The mixture was stirred at 0° C. for 30 min,2,2-dimethyloxirane (0.11 mL) was added, and the mixture was stirred at90° C. for 24 hr. The reaction mixture was added to 1 M hydrochloricacid, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.14 g, 61%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.11 (t, J=7.35 Hz, 3H) 1.35 (s, 6H)1.73-1.88 (m, 2H) 3.06-3.18 (m, 2H) 3.83 (s, 2H) 4.07 (s, 2H) 7.04-7.12(m, 2H) 7.31-7.53 (m, 8H) 7.58-7.67 (m, 1H) 7.75 (dd, J=7.72, 0.94 Hz,1H) 7.86 (s, 1H)

Reference Example 3084′-({4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(retention time: short)

A mixture of4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(1.0 g), butane-2,3-diol (0.38 g), 4-methylbenzenesulfonic acid (0.042g) and toluene (20 mL) was heated with a Dean-Stark apparatus underreflux for 9 hr. The reaction mixture was added to saturated aqueoussodium hydrogen carbonate solution, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was dissolved in tetrahydrofuran (20mL), sodium cyanoborohydride (0.67 g) and boron trifluoride etherate(1.3 mL) were added, and the mixture was heated under reflux for 7 hr.The reaction mixture was added to saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. 60% of the residue was dissolved in acetonitrile (3 mL),Dess-Martin periodinane (1.0 g) was added, and the mixture was stirredat room temperature for 2 hr. Saturated aqueous sodium hydrogencarbonate solution and aqueous sodium thiosulfate solution were added tothe reaction mixture, and the mixture was stirred for 1 hr. The solventwas evaporated under reduced pressure, and the residue was extractedwith ethyl acetate. The organic layer was washed with saturated brine,and dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure, and the residue was dissolved in tetrahydrofuran(3 mL), methylmagnesium bromide (1.9 mL, 1.0 M tetrahydrofuran solution)was added dropwise at 0° C., and the mixture was stirred at roomtemperature for 18 hr. The reaction mixture was added to 1 Mhydrochloric acid, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a racemate (0.19 g, 27%).

The obtained racemate (0.16 g) was resolved using a chiral column togive the title compound as a colorless solid (0.088 g, 99.9% ee, 54%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.35 Hz, 3H) 1.09-1.14 (m,6H) 1.17 (s, 3H) 1.32-1.55 (m, 2H) 1.66-1.87 (m, 4H) 2.08-2.25 (m, 2H)2.43 (s, 1H) 2.55-2.83 (m, 2H) 2.97-3.09 (m, 2H) 3.34 (q, J=6.40 Hz, 1H)3.42-3.58 (m, 1H) 4.01 (s, 2H) 4.95-5.17 (m, 1H) 7.32-7.52 (m, 6H)7.58-7.68 (m, 1H) 7.75 (dd, J=7.72, 0.94 Hz, 1H) 7.92 (s, 1H)

Enantiomeric Excess Measurement Condition

CHIRALPACK AD-H 4.6 mm ID×150 mL LF001

Hexane/2-Propanol=500/500

0.5 ml/min

retention time 20.28 min

Reference Example 3094′-({4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(retention time: long)

The racemate (0.16 g) of the title compound obtained in ReferenceExample 308 was resolved using a chiral column to give the titlecompound as a colorless solid (0.071 g, 99.9% ee, 44%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.35 Hz, 3H) 1.09-1.14 (m,6H) 1.17 (s, 3H) 1.32-1.55 (m, 2H) 1.66-1.87 (m, 4H) 2.08-2.25 (m, 2H)2.43 (s, 1H) 2.55-2.83 (m, 2H) 2.97-3.09 (m, 2H) 3.34 (q, J=6.40 Hz, 1H)3.42-3.58 (m, 1H) 4.01 (s, 2H) 4.95-5.17 (m, 1H) 7.32-7.52 (m, 6H)7.58-7.68 (m, 1H) 7.75 (dd, J=7.72, 0.94 Hz, 1H) 7.92 (s, 1H)

Enantiomeric Excess Measurement Condition

CHIRALPACK AD-H 4.6 mm ID×150 mL LF001

Hexane/2-Propanol=500/500

0.5 ml/min

retention time 25.43 min

Reference Example 3104′-({4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-{[2-methyl-5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(5.0 g), butane-2,3-diol (1.8 g), 4-methylbenzenesulfonic acid (0.19 g)and toluene (20 mL) was heated with a Dean-Stark apparatus under refluxfor 8 hr. The reaction mixture was added to saturated aqueous sodiumhydrogen carbonate solution, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. 40% of the residue was dissolved in tetrahydrofuran(30 mL), sodium cyanoborohydride (1.3 g) and boron trifluoride etherate(2.6 mL) were added, and the mixture was heated under reflux for 13 hr.The reaction mixture was added to saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The residue obtained by purification by silica gel columnchromatography was dissolved in acetonitrile (10 mL), Dess-Martinperiodinane (1.7 g) was added, and the mixture was stirred at roomtemperature for 14 hr. Saturated aqueous sodium hydrogen carbonatesolution and aqueous sodium thiosulfate solution were added to thereaction mixture, and the mixture was stirred for 3 hr. The solvent wasevaporated under reduced pressure, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was dissolved in tetrahydrofuran (10mL). Methylmagnesium bromide (6.2 mL, 1.0 M tetrahydrofuran solution)was added dropwise at 0° C., and the mixture was stirred at roomtemperature for 4 hr. The reaction mixture was added to 1 M hydrochloricacid, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.24 g, 10%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.04 (t, J=7.35 Hz, 3H) 1.09-1.15 (m,6H) 1.17 (s, 3H) 1.32-1.56 (m, 2H) 1.64-1.84 (m, 4H) 2.06-2.23 (m, 2H)2.44 (s, 3H) 2.59-2.84 (m, 2H) 2.91-3.03 (m, 2H) 3.34 (q, J=6.22 Hz, 1H)3.39-3.59 (m, 1H) 3.98 (s, 2H) 4.91-5.09 (m, 1H) 7.30-7.52 (m, 6 H)7.58-7.67 (m, 1H) 7.74 (dd, J=7.72, 0.94 Hz, 1H)

Reference Example 3114′-({4-[trans-4-(2-hydroxy-1-methylethoxy)-4-methylcyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-{[2-methyl-5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(1.7 g), propane-1,2-diol (0.55 g), 4-methylbenzenesulfonic acid (0.070g) and toluene (20 mL) was heated with a Dean-Stark apparatus underreflux for 5 hr. The reaction mixture was added to saturated aqueoussodium hydrogen carbonate solution, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was dissolved in methylene chloride(20 mL). Trimethylaluminum (20 mL, 1.4M hexane solution) was added underan argon atmosphere, and the mixture was stirred at 40° C. for 64 hr.The reaction mixture was cooled to 0° C., and diluted with ethylacetate. Methanol was gradually added, and the reaction wasdiscontinued. The mixture was added to 1 M hydrochloric acid, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.63 g, 31%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.04 (t, J=7.35 Hz, 3H) 1.13 (d, J=6.22Hz, 3H) 1.45 (s, 3H) 1.60-1.93 (m, 8H) 1.99 (dd, J=8.29, 4.71 Hz, 1H)2.43 (s, 3H) 2.70-2.90 (m, 2H) 2.91-3.03 (m, 2H) 3.30-3.44 (m, 1H)3.44-3.55 (m, 1H) 3.80-3.94 (m, 1H) 3.99 (s, 2H) 4.84-5.12 (m, 1H)7.31-7.54 (m, 6H) 7.57-7.67 (m, 1H) 7.70-7.78 (m, 1H)

Reference Example 3124′-({4-[trans-4-(2-hydroxy-1-methylpropoxy)-4-methylcyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a mixture of4′-({4-[trans-4-(2-hydroxy-1-methylethoxy)-4-methylcyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.63 g), triethylamine (0.80 mL) and dimethyl sulfoxide (3 mL) wasadded dropwise a solution of sulfur trioxide-pyridine complex (0.54 g)in dimethyl sulfoxide (3 mL), and the mixture was stirred at roomtemperature for 12 hr.

The reaction mixture was added to 1 M hydrochloric acid, and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was dissolved intetrahydrofuran (10 mL). Methylmagnesium bromide (2.3 mL, 1.0 Mtetrahydrofuran solution) was added dropwise at 0° C., and the mixturewas stirred at room temperature for 2 hr. Methylmagnesium bromide (1.1mL, 1.0 M tetrahydrofuran solution) was added, and the mixture wasstirred at room temperature for 2 hr. The reaction mixture was added to1 M hydrochloric acid, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.34 g,52%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.04 (t, J=7.35 Hz, 3H) 1.07-1.11 (m,4.2H) 1.12-1.18 (m, 1.8H) 1.43 (s, 2.1H) 1.46 (s, 0.9H) 1.62-1.90 (m,8H) 2.25 (d, J=3.77 Hz, 1H) 2.43 (s, 3H) 2.71-2.89 (m, 2H) 2.90-3.02 (m,2H) 3.41-3.53 (m, 0.6H) 3.62-3.82 (m, 1.4H) 3.99 (s, 2H) 4.89-5.08 (m,1H) 7.31-7.53 (m, 6H) 7.58-7.67 (m, 1H) 7.75 (dd, J=7.63, 0.85 Hz, 1H)

Reference Example 3134′-({4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)-4-methylcyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a mixture of4′-({4-[trans-4-(2-hydroxy-1-methylpropoxy)-4-methylcyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.34 g), triethylamine (0.42 mL) and dimethyl sulfoxide (2 mL) wasadded dropwise a solution of sulfur trioxide-pyridine complex (0.28 g)in dimethyl sulfoxide (2 mL), and the mixture was stirred at roomtemperature for 14 hr. The reaction mixture was added to 1 Mhydrochloric acid, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The residue obtained by purification by silica gel column chromatographywas dissolved in tetrahydrofuran (3 mL), methylmagnesium bromide (1.0mL, 1.0 M tetrahydrofuran solution) was added dropwise at 0° C., and themixture was stirred at room temperature for 2 hr. Methylmagnesiumbromide (0.50 mL, 1.0 M tetrahydrofuran solution) was added, and themixture was stirred at room temperature for 4 hr. The reaction mixturewas added to 1 M hydrochloric acid, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The residue obtained by purification by silica gelcolumn chromatography was dissolved in tetrahydrofuran (3 mL),methylmagnesium bromide (3.0 mL, 1.0 M tetrahydrofuran solution) wasadded dropwise, and the mixture was stirred at room temperature for 14hr. The reaction mixture was added to 1 M hydrochloric acid, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.17 g, 50%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.04 (t, J=7.35 Hz, 3H) 1.09-1.15 (m,6H) 1.17 (s, 3H) 1.45 (s, 3H) 1.63-1.92 (m, 8H) 2.43 (s, 3H) 2.45 (br.s., 1H) 2.71-2.90 (m, 2H) 2.91-3.02 (m, 2H) 3.56 (q, J=6.22 Hz, 1H) 3.99(s, 2H) 4.84-5.07 (m, 1H) 7.31-7.53 (m, 6H) 7.57-7.67 (m, 1H) 7.74 (dd,J=7.72, 0.94 Hz, 1H)

Reference Example 3144′-({4-[trans-4-(2-hydroxy-1-methylethoxy)-4-methylcyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.50 g), propane-1,2-diol (0.24 g), 4-methylbenzenesulfonic acid (0.021g) and toluene (20 mL) was heated with a Dean-Stark apparatus underreflux for 6 hr. The reaction mixture was added to saturated aqueoussodium hydrogen carbonate solution, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was dissolved in methylene chloride (2mL), trimethylaluminum (6.1 mL, 1.4M hexane solution) was added under anargon atmosphere, and the mixture was stirred at 40° C. for 14 hr. Thereaction mixture was cooled to 0° C., methanol was gradually added, andthe reaction was discontinued. The mixture was added to 1 M hydrochloricacid, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.13 g, 22%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.38 Hz, 3H) 1.13 (d, J=6.44Hz, 3H) 1.46 (s, 3H) 1.61-1.93 (m, 8H) 1.98 (dd, J=7.95, 4.54 Hz, 1H)2.71-2.90 (m, 2H) 2.95-3.07 (m, 2 H) 3.33-3.43 (m, 1H) 3.45-3.55 (m, 1H)3.81-3.94 (m, 1H) 4.02 (s, 2H) 4.96-5.15 (m, 1H) 7.33-7.52 (m, 6H)7.59-7.66 (m, 1H) 7.72-7.78 (m, 1H) 7.92 (s, 1H)

Reference Example 3154′-({4-[trans-4-(2-hydroxy-1-methylpropoxy)-4-methylcyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a mixture of4′-({4-[trans-4-(2-hydroxy-1-methylethoxy)-4-methylcyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(1.8 g), triethylamine (2.4 mL) and dimethyl sulfoxide (10 mL) was addeddropwise a solution of sulfur trioxide-pyridine complex (1.6 g) indimethyl sulfoxide (10 mL), and the mixture was stirred at roomtemperature for 1.5 hr. The reaction mixture was added to 1 Mhydrochloric acid, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was dissolved in tetrahydrofuran (20 mL).Methylmagnesium bromide (6.9 mL, 1.0 M tetrahydrofuran solution) wasadded dropwise at 0° C., and the mixture was stirred at 0° C. for 2 hrand then at room temperature for 1 hr. The reaction mixture was added to1 M hydrochloric acid, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (1.4 g,75%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.00-1.21 (m, 9H) 1.43 (s, 2.25H) 1.47(s, 0.75H) 1.62-1.95 (m, 8H) 2.25 (d, J=3.41 Hz, 0.75H) 2.62 (s, 0.25H)2.67-2.89 (m, 2H) 2.94-3.09 (m, 2H) 3.40-3.56 (m, 0.5H) 3.62-3.86 (m,1.5H) 4.02 (s, 2H) 4.95-5.15 (m, 1H) 7.33-7.55 (m, 6H) 7.58-7.69 (m, 1H)7.75 (d, J=6.82 Hz, 1H) 7.92 (s, 1H)

Reference Example 3164′-({4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)-4-methylcyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a mixture of4′-({4-[trans-4-(2-hydroxy-1-methylpropoxy)-4-methylcyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(1.4 g), triethylamine (1.8 mL) and dimethyl sulfoxide (8 mL) was addeddropwise a solution of sulfur trioxide-pyridine complex (1.2 g) indimethyl sulfoxide (7 mL), and the mixture was stirred at roomtemperature for 2 hr. The reaction mixture was added to 1 M hydrochloricacid, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The residue obtained by purification by silica gel column chromatographywas dissolved in tetrahydrofuran (15 mL), methylmagnesium bromide (10mL, 1.0 M tetrahydrofuran solution) was added dropwise at 0° C., and themixture was stirred at room temperature for 16 hr. The reaction mixturewas added to 1 M hydrochloric acid, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (1.0 g,67%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.35 Hz, 3H) 1.10-1.15 (m,6H) 1.17 (s, 3H) 1.46 (s, 3H) 1.61-1.94 (m, 8H) 2.44 (s, 1H) 2.69-2.92(m, 2H) 2.95-3.08 (m, 2H) 3.56 (q, J=6.15 Hz, 1H) 4.02 (s, 2H) 4.93-5.16(m, 1H) 7.32-7.55 (m, 6H) 7.57-7.69 (m, 1H) 7.75 (dd, J=7.82, 0.85 Hz,1H) 7.92 (s, 1H)

Reference Example 3174′-({4-[4-hydroxy-4-(tetrahydro-2H-pyran-4-yl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a mixture of magnesium (0.10 g) and tetrahydrofuran (1 mL) were added4-chlorotetrahydro-2H-pyran (0.050 g) and 1,2-dibromoethane (10 drops)under an argon atmosphere. The mixture was heated to initiate thereaction, a solution of 4-chlorotetrahydro-2H-pyran (0.46 g) intetrahydrofuran (5 mL) was added dropwise at 50° C., and the mixture wasstirred at 50° C. for 4 hr. The reaction mixture was cooled to 0° C., asolution of4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.50 g) in tetrahydrofuran (5 mL) was added dropwise, and the mixturewas stirred at room temperature for 18 hr. The reaction mixture wasadded to 1 M hydrochloric acid, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography and HPLC to give the title compound as a colorless solid(0.12 g, 20%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.07 (t, J=7.38 Hz, 3H) 1.48-1.87 (m,13H) 2.79-2.99 (m, 2H) 2.99-3.11 (m, 2H) 3.41-3.54 (m, 2H) 4.03 (s, 2H)4.08-4.23 (m, 2H) 4.93-5.10 (m, 1H) 7.32-7.53 (m, 6H) 7.59-7.68 (m, 1H)7.73-7.79 (m, 1H) 8.02 (s, 1H)

Reference Example 318 tert-butyl2-{[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetyl}hydrazinecarboxylate

A mixture of[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]aceticacid (0.77 g), tert-butyl hydrazinecarboxylate (0.23 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.34 g),1-hydroxybenzotriazole (0.24 g) and N,N-dimethylformaldehyde (8 mL) wasstirred at room temperature for 12 hr. Ethyl acetate and water wereadded to the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.69 g,72%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.35 Hz, 3H) 1.39-1.89 (m,6H) 1.48 (s, 9H) 2.10-2.26 (m, 2H) 2.61-2.81 (m, 2H) 2.95-3.08 (m, 2H)3.43-3.61 (m, 1H) 4.01 (s, 2H) 4.13 (s, 2H) 4.97-5.18 (m, 1H) 7.32-7.52(m, 6H) 7.58-7.68 (m, 1H) 7.75 (dd, J=7.72, 0.94 Hz, 1H) 7.91 (s, 1H)8.08-8.16 (m, 1H)

Reference Example 3194′-({4-[trans-4-(1,3,4-oxadiazol-2-ylmethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]aceticacid (0.45 g), tert-butyl hydrazinecarboxylate (0.13 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.19 g),1-hydroxybenzotriazole (0.13 g) and N,N-dimethylformaldehyde (5 mL) wasstirred at room temperature for 13 hr. Ethyl acetate and water wereadded to the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, the residue was dissolved in trifluoroacetic acid (5mL), and the mixture was stirred at room temperature for 1 hr. 1 MAqueous sodium hydroxide solution was added to the reaction mixture, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasmixed with ethyl orthoformate (0.37 g), methanesulfonic acid (0.016 g)and tetrahydrofuran (7 mL), and the mixture was heated under reflux for2 hr. The solvent was evaporated under reduced pressure, and the residuewas purified by silica gel column chromatography to give the titlecompound as a colorless solid (0.17 g, 37%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.35 Hz, 3H) 1.40-1.89 (m,6H) 2.13-2.28 (m, 2H) 2.61-2.85 (m, 2H) 2.94-3.10 (m, 2H) 3.53-3.70 (m,1H) 4.01 (s, 2H) 4.81 (s, 2H) 4.97-5.18 (m, 1H) 7.32-7.53 (m, 6H)7.59-7.67 (m, 1H) 7.75 (dd, J=7.82, 0.85 Hz, 1H) 7.92 (s, 1H) 8.44 (s,1H)

Reference Example 3204′-{[5-oxo-7-propyl-4-(4,5,6,7-tetrahydro-1H-indazol-5-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(1.0 g), 1,1-dimethoxy-N,N-dimethylmethanamine (2.5 mL) andN,N-dimethylformaldehyde (2.5 mL) was stirred at 85° C. for 11 hr. Ethylacetate and water were added to the reaction mixture, and the mixturewas extracted with ethyl acetate. The organic layer was washed withwater and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was dissolved in ethanol (10 mL). Hydrazine monohydrate (1 mL)was added, and the mixture was heated under reflux for 1.5 hr. Ethylacetate and water were added to the reaction mixture. After evaporationof the solvent under reduced pressure, the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.74 g,71%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.08 (t, J=7.35 Hz, 3H) 1.66-1.85 (m,2H) 1.97-2.09 (m, 1H) 2.73-3.26 (m, 6H) 3.60-3.74 (m, 1H) 4.04 (s, 2H)5.37-5.56 (m, 1H) 7.32 (s, 1H) 7.35-7.54 (m, 6H) 7.58-7.70 (m, 1H) 7.75(dd, J=7.82, 0.85 Hz, 1H) 7.91 (s, 1H)

Reference Example 3214′-({4-[1-(2-hydroxy-2-methylpropyl)-4,5,6,7-tetrahydro-1H-indazol-5-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-{[5-oxo-7-propyl-4-(4,5,6,7-tetrahydro-1H-indazol-5-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.36 g), sodium hydride (0.044 g) and N,N-dimethylacetamide (3 mL) wasstirred at 0° C. for 5 min and then at room temperature for 20 min.2,2-Dimethyloxirane (0.65 mL) was added, and the mixture was stirred at120° C. for 1.5 hr. Ethyl acetate and water were added to the reactionmixture, and the mixture was extracted with ethyl acetate. The organiclayer was washed with water and then with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.035 g,8%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.08 (t, J=7.35 Hz, 3H) 1.12 (s, 3H)1.16 (s, 3H) 1.64-1.86 (m, 2H) 2.00-2.12 (m, 1H) 2.70-2.93 (m, 3H)2.98-3.11 (m, 2H) 3.11-3.27 (m, 1H) 3.57-3.74 (m, 1H) 3.83-3.97 (m, 2H)4.04 (s, 2H) 4.52 (s, 1H) 5.31-5.52 (m, 1H) 7.31 (s, 1H) 7.35-7.55 (m,6H) 7.58-7.68 (m, 1H) 7.75 (dd, J=7.72, 0.94 Hz, 1H) 7.91 (s, 1H)

Reference Example 3224′-({4-[2-(2-hydroxy-2-methylpropyl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-{[5-oxo-7-propyl-4-(4,5,6,7-tetrahydro-1H-indazol-5-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.36 g), sodium hydride (0.044 g) and N,N-dimethylacetamide (3 mL) wasstirred at 0° C. for 5 min and then at room temperature for 20 min.2,2-Dimethyloxirane (0.65 mL) was added, and the mixture was stirred at120° C. for 1.5 hr. Ethyl acetate and water were added to the reactionmixture, and the mixture was extracted with ethyl acetate. The organiclayer was washed with water and then with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.047 g,11%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.08 (t, J=7.35 Hz, 3H) 1.15 (s, 6H)1.65-1.83 (m, 2H) 1.97-2.08 (m, 1H) 2.74-3.23 (m, 6H) 3.60-3.74 (m, 1H)3.97 (s, 2H) 4.04 (s, 2H) 4.11 (s, 1H) 5.35-5.54 (m, 1H) 7.12 (s, 1H)7.36-7.53 (m, 6H) 7.59-7.67 (m, 1H) 7.75 (dd, J=7.72, 0.94 Hz, 1H) 7.92(s, 1H)

Reference Example 323N′-acetyl-2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetohydrazide

A mixture of[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]aceticacid (0.50 g), acetohydrazide (0.085 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.21 g),1-hydroxybenzotriazole (0.15 g) and N,N-dimethylformaldehyde (5 mL) wasstirred at room temperature for 22 hr. Ethyl acetate and water wereadded to the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.42 g,76%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.38 Hz, 3H) 1.42-1.89 (m,6H) 2.08 (s, 3H) 2.15-2.29 (m, 2H) 2.58-2.81 (m, 2H) 2.96-3.09 (m, 2H)3.45-3.62 (m, 1H) 4.01 (s, 2H) 4.14 (s, 2H) 4.93-5.21 (m, 1H) 7.32-7.53(m, 6H) 7.58-7.69 (m, 1H) 7.75 (d, J=7.57 Hz, 1H) 7.91 (s, 1H) 8.01-8.10(m, 1H) 8.79 (d, J=5.30 Hz, 1H)

Reference Example 3244′-[(4-{trans-4-[(5-methyl-1,3,4-oxadiazol-2-yl)methoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

A mixture ofN′-acetyl-2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetohydrazide(0.42 g), 4-methylbenzenesulfonyl chloride (0.16 g) and pyridine (5 mL)was stirred at 110° C. for 16 hr. 4-Methylbenzenesulfonyl chloride(0.083 g) was added, and the mixture was stirred at 110° C. for 8 hr.Ethyl acetate and 1 M hydrochloric acid were added to the reactionmixture, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.24 g, 60%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.35 Hz, 3H) 1.41-1.58 (m,2H) 1.65-1.89 (m, 4H) 2.10-2.29 (m, 2H) 2.56 (s, 3H) 2.61-2.82 (m, 2H)2.95-3.11 (m, 2H) 3.49-3.67 (m, 1H) 4.01 (s, 2H) 4.72 (s, 2H) 4.96-5.17(m, 1H) 7.32-7.53 (m, 6H) 7.57-7.68 (m, 1H) 7.75 (dd, J=7.72, 0.75 Hz,1H) 7.90 (s, 1H)

Reference Example 3254′-({5-oxo-4-[trans-4-(2-oxoethoxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a mixture of4′-({4-[trans-4-(2-hydroxyethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(1.3 g), triethylamine (1.8 mL) and dimethyl sulfoxide (8 mL) was addeddropwise a solution of sulfur trioxide-pyridine complex (1.2 g) indimethyl sulfoxide (7 mL), and the mixture was stirred at roomtemperature for 1.5 hr. A solution of triethylamine (1.8 mL) and sulfurtrioxide-pyridine complex (1.2 g) in dimethyl sulfoxide (5 mL) wasadded, and the mixture was stirred at room temperature for 16 hr. Thereaction mixture was added to 1 M hydrochloric acid, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.31 g, 23%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.38 Hz, 3H) 1.42-1.62 (m,2H) 1.63-1.90 (m, 4H) 2.14-2.29 (m, 2H) 2.60-2.83 (m, 2H) 2.95-3.09 (m,2H) 3.44-3.59 (m, 1H) 4.01 (s, 2H) 4.13 (s, 2H) 4.96-5.20 (m, 1H)7.32-7.53 (m, 6H) 7.58-7.68 (m, 1H) 7.75 (d, J=7.57 Hz, 1H) 7.91 (s, 1H)9.75 (s, 1H)

Reference Example 3264′-({5-oxo-7-propyl-4-[trans-4-(3,3,3-trifluoro-2-hydroxypropoxy)cyclohexyl]-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

4′-({5-Oxo-4-[trans-4-(2-oxoethoxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.31 g) and trimethyl(trifluoromethyl)silane (0.12 g) were dissolved intetrahydrofuran (5 mL), tetrabutylammonium fluoride (0.74 mL, 1.0 Mtetrahydrofuran solution) was added dropwise, and the mixture wasstirred at room temperature for 16 hr. 1 M Hydrochloric acid was addedto the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.054 g,15%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.38 Hz, 3H) 1.38-1.61 (m,2H) 1.67-1.88 (m, 4H) 2.12-2.26 (m, 2H) 2.61-2.81 (m, 2H) 2.85-2.94 (m,1H) 2.98-3.08 (m, 2H) 3.43-3.58 (m, 1H) 3.63-3.72 (m, 1H) 3.73-3.81 (m,1H) 4.01 (s, 2H) 4.99-5.15 (m, 1H) 7.33-7.53 (m, 6H) 7.59-7.68 (m, 1H)7.75 (d, J=7.95 Hz, 1H) 7.91 (s, 1H)

Reference Example 3274′-({5-oxo-4-[trans-4-(2-oxobutoxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

2-[(trans-4-{6-[(2′-Cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide(1.0 g) was dissolved in tetrahydrofuran (10 mL), ethylmagnesium bromide(1.7 mL, 3.0 M diethyl ether solution) was added dropwise, and themixture was stirred at room temperature for 15 hr. The reaction mixturewas added to 1 M hydrochloric acid, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.64 g,67%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.01-1.11 (m, 6H) 1.43-1.56 (m, 2H)1.68-1.88 (m, 4H) 2.13-2.27 (m, 2H) 2.51 (q, J=7.45 Hz, 2H) 2.61-2.80(m, 2H) 2.98-3.10 (m, 2H) 3.37-3.52 (m, 1H) 4.01 (s, 2H) 4.10 (s, 2H)4.97-5.17 (m, 1H) 7.33-7.54 (m, 6H) 7.58-7.68 (m, 1H) 7.75 (d, J=7.57Hz, 1H) 7.91 (s, 1H)

Reference Example 3284′-({4-[trans-4-(2-hydroxybutoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

4′-({5-Oxo-4-[trans-4-(2-oxobutoxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.64 g) was dissolved in tetrahydrofuran (3 mL) and methanol (6 mL),and sodium tetrahydroborate (0.060 g) was added at 0° C. The reactionmixture was stirred at 0° C. for 2 hr. Saturated aqueous ammoniumchloride solution was added to the reaction mixture, the solvent wasevaporated under reduced pressure, and the residue was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.48 g,74%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.97 (t, J=7.44 Hz, 3H) 1.06 (t, J=7.35Hz, 3H) 1.35-1.54 (m, 4H) 1.64-1.87 (m, 4H) 2.10-2.26 (m, 2H) 2.35 (d,J=3.20 Hz, 1H) 2.58-2.81 (m, 2H) 2.96-3.09 (m, 2H) 3.30 (dd, J=9.23,8.10 Hz, 1H) 3.38-3.50 (m, 1H) 3.55 (dd, J=9.42, 3.01 Hz, 1H) 3.61-3.75(m, 1H) 4.01 (s, 2H) 4.98-5.17 (m, 1H) 7.32-7.53 (m, 6H) 7.58-7.67 (m,1H) 7.75 (dd, J=7.72, 0.94 Hz, 1H) 7.91 (s, 1H)

Reference Example 3294′-[(4-{trans-4-[(1-{[tert-butyl(dimethyl)silyl]oxy}cyclopropyl)methoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

4′-({5-Oxo-4-[trans-4-(2-oxopropoxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.55 g) was dissolved in methylene chloride (4 mL) under an argonatmosphere, N,N-diisopropylethylamine (0.44 mL) was added dropwise at−78° C., and the mixture was stirred at −78° C. for 40 min.tert-Butyl(dimethyl)silyl trifluoromethanesulfonate (0.58 mL) was added,and the mixture was stirred at −78° C. for 1.5 hr. The reaction mixturewas added to saturated aqueous sodium hydrogen carbonate solution, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue obtainedby purification by silica gel column chromatography was dissolved inmethylene chloride (10 mL), and the mixture was added dropwise to amixture of diethylzinc (6.5 mL, 1.0 M hexane solution),chloroiodomethane (1.1 g) and methylene chloride (10 mL) stirred at 0°C. for 10 min under an argon atmosphere in advance. The mixture wasslowly warmed to room temperature, and the mixture was stirred at roomtemperature for 2 hr. The reaction mixture was added to saturatedaqueous ammonium chloride solution, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.24 g,40%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.12 (s, 6H) 0.52-0.62 (m, 2H)0.68-0.76 (m, 2H) 0.85 (s, 9H) 1.06 (t, J=7.35 Hz, 3H) 1.39-1.55 (m, 2H)1.64-1.85 (m, 4H) 2.08-2.25 (m, 2H) 2.58-2.79 (m, 2H) 2.97-3.08 (m, 2H)3.34-3.44 (m, 1H) 3.46 (s, 2H) 4.01 (s, 2H) 4.96-5.16 (m, 1H) 7.33-7.56(m, 6H) 7.57-7.68 (m, 1H) 7.75 (dd, J=7.72, 0.94 Hz, 1H) 7.92 (s, 1H)

Reference Example 3304′-[(5-oxo-4-{trans-4-[(2-oxobut-3-en-1-yl)oxy]cyclohexyl}-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

2-[(trans-4-{6-[(2′-Cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide(0.50 g) was dissolved in tetrahydrofuran (5 mL), vinylmagnesium bromide(2.6 mL, 1.0 M tetrahydrofuran solution) was added dropwise, and themixture was stirred at room temperature for 24 hr. The reaction mixturewas added to 1 M hydrochloric acid, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.21 g,46%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.38 Hz, 3H) 1.41-1.55 (m,2H) 1.65-1.87 (m, 4H) 2.15-2.30 (m, 2H) 2.60-2.79 (m, 2H) 2.97-3.09 (m,2H) 3.42-3.55 (m, 1H) 4.01 (s, 2H) 4.31 (s, 2H) 5.00-5.16 (m, 1H) 5.84(dd, J=10.60, 1.51 Hz, 1H) 6.32-6.41 (m, 1H) 6.54-6.67 (m, 1H) 7.31-7.56(m, 6H) 7.58-7.68 (m, 1H) 7.75 (d, J=7.95 Hz, 1H) 7.91 (s, 1H)

Reference Example 3314′-[(4-{trans-4-[(2-hydroxybut-3-en-1-yl)oxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

Under an argon atmosphere, a mixture of4′-[(5-oxo-4-{trans-4-[(2-oxobut-3-en-1-yl)oxy]cyclohexyl}-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.21 g), cerium chloride anhydrous (0.15 g), tetrahydrofuran (4 mL) andmethanol (2 mL) was stirred at 0° C. for 10 min, and the mixture wascooled to −78° C. Sodium tetrahydroborate (0.026 g) was added, and themixture was stirred at −78° C. for 1 hr. The reaction mixture was addedto saturated aqueous ammonium chloride solution, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.035 g, 16%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.35 Hz, 3H) 1.36-1.56 (m,2H) 1.65-1.87 (m, 4H) 2.12-2.29 (m, 2H) 2.48 (d, J=3.20 Hz, 1H)2.61-2.80 (m, 2H) 2.98-3.09 (m, 2H) 3.35 (dd, J=9.51, 8.19 Hz, 1H)3.41-3.54 (m, 1H) 3.58 (dd, J=9.51, 3.30 Hz, 1H) 4.01 (s, 2H) 4.23-4.38(m, 1H) 4.99-5.14 (m, 1H) 5.17-5.42 (m, 2H) 5.84 (ddd, J=17.19, 10.50,5.65 Hz, 1H) 7.33-7.55 (m, 6H) 7.59-7.68 (m, 1H) 7.75 (dd, J=7.72, 0.94Hz, 1H) 7.92 (s, 1H)

Reference Example 3324′-({4-[trans-4-(2-cyclopropyl-2-oxoethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

2-[(trans-4-{6-[(2′-Cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide(0.32 g) was dissolved in tetrahydrofuran (4 mL), cyclopropylmagnesiumbromide (3.3 mL, 0.5M tetrahydrofuran solution) was added dropwise, andthe mixture was stirred at room temperature for 4 hr. The reactionmixture was added to 1 M hydrochloric acid, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.23 g, 75%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.87-1.01 (m, 2H) 1.02-1.15 (m, 5H)1.45-1.63 (m, 2H) 1.64-1.89 (m, 4H) 2.10-2.32 (m, 3H) 2.61-2.82 (m, 2H)2.96-3.11 (m, 2H) 3.37-3.60 (m, 1H) 4.01 (s, 2H) 4.23 (s, 2H) 5.00-5.14(m, 1H) 7.31-7.54 (m, 6H) 7.58-7.68 (m, 1H) 7.74 (d, J=7.95 Hz, 1H) 7.91(s, 1H)

Reference Example 3334′-({4-[trans-4-(2-cyclopropyl-2-hydroxyethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

4′-({4-[trans-4-(2-Cyclopropyl-2-oxoethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.23 g) was dissolved in tetrahydrofuran (2 mL) and methanol (4 mL),sodium tetrahydroborate (0.027 g) was added at 0° C., and the mixturewas stirred at 0° C. for 1 hr. Saturated aqueous ammonium chloridesolution was added to the reaction mixture, the solvent was evaporatedunder reduced pressure, and the residue was extracted with ethylacetate. The organic layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.17 g,72%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.16-0.29 (m, 1H) 0.31-0.67 (m, 3H)0.77-0.93 (m, 1H) 1.06 (t, J=7.38 Hz, 3H) 1.37-1.55 (m, 2H) 1.65-1.91(m, 4H) 2.11-2.28 (m, 2H) 2.40 (s, 1H) 2.57-2.84 (m, 2H) 2.96-3.13 (m,3H) 3.37-3.56 (m, 2H) 3.66 (dd, J=9.47, 2.65 Hz, 1H) 4.01 (s, 2H)4.95-5.23 (m, 1H) 7.32-7.53 (m, 6H) 7.58-7.68 (m, 1H) 7.74 (d, J=7.57Hz, 1H) 7.91 (s, 1H)

Reference Example 3344′-({5-oxo-7-propyl-4-[trans-4-(3,3,3-trifluoro-2-hydroxy-2-methylpropoxy)cyclohexyl]-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

4′-({5-Oxo-4-[trans-4-(2-oxopropoxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.30 g) and trimethyl(trifluoromethyl)silane (0.20 g) were dissolved intetrahydrofuran (3 mL), tetrabutylammonium fluoride (0.22 mL, 1.0 Mtetrahydrofuran solution) was added dropwise at 0° C., and the mixturewas stirred at 0° C. for 1 hr. Trimethyl(trifluoromethyl)silane (0.20 g)and tetrabutylammonium fluoride (0.22 mL, 1.0 M tetrahydrofuransolution) were added, and the mixture was stirred at 0° C. for 1 hr andthen at room temperature for 16 hr. The reaction mixture was added to 1M hydrochloric acid, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.092 g,27%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.38 Hz, 3H) 1.34 (s, 3H)1.40-1.56 (m, 2H) 1.64-1.87 (m, 4H) 2.11-2.26 (m, 2H) 2.60-2.80 (m, 2H)2.97-3.08 (m, 2H) 3.36-3.57 (m, 2H) 3.72 (d, J=9.84 Hz, 1H) 4.01 (s, 2H)4.95-5.15 (m, 1H) 7.32-7.52 (m, 6H) 7.59-7.68 (m, 1H) 7.74 (d, J=7.95Hz, 1H) 7.91 (s, 1H)

Reference Example 3354′-({4-[trans-4-(oxiran-2-ylmethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-({5-oxo-4-[4-(prop-2-en-1-yloxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(1.1 g), m-chloroperbenzoic acid (1.8 g) and acetonitrile (10 mL) wasstirred at 50° C. for 15 hr. Saturated aqueous sodium hydrogen carbonatesolution and aqueous sodium thiosulfate solution were added to thereaction mixture, and the mixture was stirred for 30 min. The solventwas evaporated under reduced pressure, and the residue was extractedwith ethyl acetate. The organic layer was washed with saturated brine,and dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography to give the title compound as a colorless solid(0.25 g, 20%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.38 Hz, 3H) 1.37-1.56 (m,2H) 1.68-1.88 (m, 4H) 2.09-2.31 (m, 2H) 2.62 (dd, J=5.30, 2.65 Hz, 1H)2.65-2.79 (m, 2H) 2.79-2.85 (m, 1H) 2.98-3.08 (m, 2H) 3.11-3.20 (m, 1H)3.40-3.58 (m, 2H) 3.74 (dd, J=11.36, 3.41 Hz, 1H) 4.01 (s, 2H) 4.95-5.15(m, 1H) 7.32-7.53 (m, 6H) 7.58-7.67 (m, 1H) 7.73 (dd, J=7.57, 1.51 Hz,1H) 7.91 (s, 1H)

Reference Example 3364′-({4-[trans-4-(3-fluoro-2-hydroxypropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-({4-[trans-4-(oxiran-2-ylmethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.25 g), potassium hydrogen fluoride (0.075 g), tetra-n-butylammoniumdihydrogentrifluoride (0.015 g) and chlorobenzene (1 mL) was stirred at120° C. for 5 hr. Potassium hydrogen fluoride (0.075 g) andtetra-n-butylammonium dihydrogentrifluoride (0.014 g) were added, andthe mixture was stirred at 120° C. for 16 hr. Toluene was added, and theprecipitate was filtered off. The filtrate was concentrated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.15 g,60%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.38 Hz, 3H) 1.36-1.54 (m,2H) 1.65-1.89 (m, 4H) 2.12-2.27 (m, 2H) 2.40 (d, J=5.30 Hz, 1H)2.60-2.82 (m, 2H) 2.96-3.10 (m, 2H) 3.39-3.51 (m, 1H) 3.52-3.67 (m, 2H)3.92-4.08 (m, 3H) 4.32-4.46 (m, 1H) 4.47-4.61 (m, 1H) 4.95-5.17 (m, 1H)7.32-7.53 (m, 6H) 7.58-7.69 (m, 1H) 7.74 (d, J=7.57 Hz, 1H) 7.91 (s, 1H)

Reference Example 3374′-({4-[trans-4-(3-fluoro-2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-({4-[trans-4-(3-fluoro-2-hydroxypropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.15 g), Dess-Martin periodinane (0.24 g) and acetonitrile (2 mL) wasstirred at room temperature for 2 hr. Saturated aqueous sodium hydrogencarbonate solution and aqueous sodium thiosulfate solution were added tothe reaction mixture. After evaporation of the solvent under reducedpressure, the residue was extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was dissolved in tetrahydrofuran (2 mL). Methylmagnesiumbromide (0.58 mL, 1.0 M tetrahydrofuran solution) was added dropwise at0° C., and the mixture was stirred at room temperature for 2 hr. Thereaction mixture was added to 1 M hydrochloric acid, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.10 g, 62%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.19 Hz, 3H) 1.21 (d, J=2.27Hz, 3H) 1.35-1.53 (m, 2H) 1.64-1.88 (m, 4H) 2.13-2.25 (m, 2H) 2.61-2.82(m, 2H) 2.98-3.09 (m, 2H) 3.31-3.57 (m, 3H) 4.01 (s, 2H) 4.12 (dd,J=32.56, 8.71 Hz, 1H) 4.34 (dd, J=32.56, 8.71 Hz, 1H) 4.94-5.16 (m, 1H)7.32-7.52 (m, 6H) 7.59-7.68 (m, 1H) 7.75 (d, J=7.95 Hz, 1H) 7.91 (s, 1H)

Reference Example 3384′-[(4-{trans-4-[(1-hydroxycyclobutyl)methoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

4′-[(4-{trans-4-[(Methylsulfanyl)methoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(1.4 g) was dissolved in dichloromethane (10 mL), and sulfuryl chloride(0.23 mL) was added at 0° C. The mixture was stirred at room temperaturefor 24 hr, and the solvent was evaporated under reduced pressure. Theresidue was mixed with cyclobutanone (0.050 g) and tetrahydrofuran (3mL), and samarium iodide (14 mL, 0.1 M tetrahydrofuran solution) wasadded dropwise at room temperature under an argon atmosphere. Themixture was stirred at room temperature for 16 hr and added to saturatedaqueous ammonium chloride solution, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.021 g,8.1%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.38 Hz, 3H) 1.37-1.87 (m,8H) 1.99-2.28 (m, 6H) 2.60-2.82 (m, 3H) 2.94-3.10 (m, 2H) 3.40-3.49 (m,1H) 3.51 (s, 2H) 4.02 (s, 2H) 4.96-5.21 (m, 1H) 7.33-7.54 (m, 6H)7.57-7.69 (m, 1H) 7.75 (d, J=7.95 Hz, 1H) 7.91 (s, 1H)

Reference Example 3394′-{[4-(trans-4-{[2-(fluoromethyl)oxiran-2-yl]methoxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-({4-[trans-4-(3-fluoro-2-hydroxypropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.33 g), Dess-Martin periodinane (0.51 g) and acetonitrile (4 mL) wasstirred at room temperature for 14 hr. Saturated aqueous sodium hydrogencarbonate solution and aqueous sodium thiosulfate solution were added tothe reaction mixture. After evaporation of the solvent under reducedpressure, the residue was extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,the residue was added to a mixture of trimethylsulfoxonium iodide (0.16g), sodium hydride (0.030 g) and dimethyl sulfoxide (5 mL) stirred atroom temperature for 1 hr in advance, and the mixture was stirred atroom temperature for 2 hr. The reaction mixture was added to water, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.17 g, 52%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.35 Hz, 3H) 1.21-1.43 (m, 2H)1.50-1.79 (m, 4H) 2.05-2.18 (m, 2H) 2.52-2.69 (m, 2H) 2.76-2.86 (m, 2H)2.90-3.04 (m, 2H) 3.33-3.46 (m, 1H) 3.55-3.73 (m, 2H) 3.99 (s, 2H)4.29-4.77 (m, 2 H) 4.85-5.02 (m, 1H) 7.35-7.44 (m, 2H) 7.46-7.52 (m, 2H)7.53-7.64 (m, 2H) 7.72-7.81 (m, 1H) 7.93 (dd, J=7.72, 0.94 Hz, 1H) 8.18(s, 1H)

Reference Example 3404′-[(4-{trans-4-[3-fluoro-2-(fluoromethyl)-2-hydroxypropoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

A mixture of4′-{[4-(trans-4-{[2-(fluoromethyl)oxiran-2-yl]methoxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.17 g), potassium hydrogen fluoride (0.15 g), tetra-n-butylammoniumdihydrogentrifluoride (0.097 g) and chlorobenzene (0.5 mL) was stirredat 120° C. for 14 hr. The precipitate was filtered off, and the filtratewas concentrated under reduced pressure. The residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.16 g, 87%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.35 Hz, 3H) 1.19-1.41 (m, 2H)1.49-1.80 (m, 4H) 2.04-2.19 (m, 2H) 2.52-2.68 (m, 2H) 2.87-3.04 (m, 2H)3.26-3.40 (m, 1H) 3.45 (s, 2H) 3.99 (s, 2H) 4.36 (d, J=47.47 Hz, 4H)4.81-5.02 (m, 1H) 5.35 (s, 1H) 7.37-7.44 (m, 2H) 7.46-7.52 (m, 2H)7.53-7.64 (m, 2H) 7.72-7.82 (m, 1H) 7.92 (dd, J=7.72, 0.94 Hz, 1H) 8.19(s, 1H)

Reference Example 3414′-[(4-{trans-4-[4-(1,3-dioxan-2-yl)-2-hydroxybutoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

2-[(trans-4-{6-[(2′-Cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide(1.5 g) was dissolved in tetrahydrofuran (15 mL),2-(1,3-dioxan-2-yl)ethylmagnesium bromide (15 mL, 0.5M tetrahydrofuransolution) was added dropwise, and the mixture was stirred at roomtemperature for 18 hr. The reaction mixture was added to 1 Mhydrochloric acid, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated aqueous sodium hydrogencarbonate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, the residue was dissolved in tetrahydrofuran (5 mL) andmethanol (10 mL), and sodium tetrahydroborate (0.16 g) was added at 0°C. The reaction mixture was stirred at 0° C. for 2 hr and then at roomtemperature for 18 hr. Saturated aqueous ammonium chloride solution wasadded to the reaction mixture, the solvent was evaporated under reducedpressure, and the residue was extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.71 g, 44%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.38 Hz, 3H) 1.30-1.91 (m,12H) 2.13-2.26 (m, 2H) 2.56-2.80 (m, 3H) 2.94-3.11 (m, 2H) 3.33 (dd,J=9.09, 7.57 Hz, 1H) 3.38-3.47 (m, 1H) 3.50 (dd, J=9.28, 3.60 Hz, 1H)3.67-3.85 (m, 3H) 4.01 (s, 2H) 4.07-4.20 (m, 2H) 4.58 (t, J=4.92 Hz, 1H)4.96-5.18 (m, 1H) 7.32-7.54 (m, 6H) 7.58-7.68 (m, 1H) 7.74 (d, J=7.57Hz, 1H) 7.91 (s, 1H)

Reference Example 3424′-[(4-{trans-4-[(2,5-dihydroxypentyl)oxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

A mixture of4′-[(4-{trans-4-[4-(1,3-dioxan-2-yl)-2-hydroxybutoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.71 g), tert-butylchlorodiphenylsilane (0.47 g), imidazole (0.11 g),N,N-dimethylaminopyridine (0.015 g) and tetrahydrofuran (8 mL) wasstirred at room temperature for 7 days. The reaction mixture was addedto 1 M hydrochloric acid, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, the residue was mixed with 3M hydrochloric acid (10mL), acetone (20 mL) and tetrahydrofuran (10 mL), and the mixture wasstirred at room temperature for 24 hr. The reaction mixture wasneutralized, the solvent was evaporated under reduced pressure, and theresidue was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure. The residue obtained bypurification by silica gel column chromatography was mixed with 3Mhydrochloric acid (10 mL) and tetrahydrofuran (20 mL), and the mixturewas stirred at 70° C. for 2 days and then at room temperature for 3days. The reaction mixture was neutralized, the solvent was evaporatedunder reduced pressure, and the residue was extracted with ethylacetate. The organic layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was dissolved in tetrahydrofuran (2mL) and methanol (4 mL). Sodium tetrahydroborate (0.034 g) was added at0° C., and the reaction mixture was stirred at 0° C. for 2 hr. Saturatedaqueous ammonium chloride solution was added to the reaction mixture,the solvent was evaporated under reduced pressure, and the residue wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was dissolved intetrahydrofuran (5 mL). Tetrabutylammonium fluoride (1.0 mL, 1.0 Mtetrahydrofuran solution) was added, and the mixture was stirred at 70°C. for 2 hr. The reaction mixture was added to 1 M hydrochloric acid,and the mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.17 g, 26%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.25 Hz, 3H) 1.20-1.81 (m, 10H)2.02-2.19 (m, 2H) 2.52-2.69 (m, 2H) 2.90-3.04 (m, 2H) 3.23-3.43 (m, 5H)3.45-3.58 (m, 1H) 3.99 (s, 2H) 4.36 (t, J=5.18 Hz, 1H) 4.48 (d, J=5.09Hz, 1H) 4.78-5.06 (m, 1H) 7.35-7.45 (m, 2H) 7.46-7.51 (m, 2H) 7.52-7.62(m, 2H) 7.72-7.83 (m, 1H) 7.92 (dd, J=7.91, 0.94 Hz, 1H) 8.18 (s, 1H)

Reference Example 3434′-({5-oxo-7-propyl-4-[trans-4-(tetrahydrofuran-2-ylmethoxy)cyclohexyl]-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

4′-[(4-{trans-4-[(2,5-Dihydroxypentyl)oxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.17 g) was dissolved in tetrahydrofuran (3 mL), triphenylphosphine(0.24 g) and then diethyl azodicarboxylate (0.40 g, 40% toluenesolution) were added, and the mixture was stirred at room temperaturefor 18 hr. The reaction mixture was added to water, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.12 g, 74%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.25 Hz, 3H) 1.13-1.96 (m, 10H)2.02-2.18 (m, 2H) 2.52-2.68 (m, 2H) 2.91-3.03 (m, 2H) 3.27-3.36 (m, 1H)3.37-3.44 (m, 2H) 3.56-3.67 (m, 1H) 3.68-3.78 (m, 1H) 3.83-3.94 (m, 1H)3.99 (s, 2H) 4.81-5.01 (m, 1H) 7.37-7.44 (m, 2H) 7.45-7.51 (m, 2H)7.52-7.68 (m, 2H) 7.74-7.82 (m, 1H) 7.93 (dd, J=7.82, 0.85 Hz, 1H) 8.18(s, 1H)

Reference Example 3444′-[(4-{trans-4-[(1-hydroxycyclopentyl)methoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

4′-[(4-{trans-4-[(Methylsulfanyl)methoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(1.0 g) was dissolved in toluene (10 mL), and sulfuryl chloride (0.16mL) was added at 0° C. The mixture was stirred at room temperature for 2hr, the precipitate was filtered off, and the filtrate was concentratedunder reduced pressure. The residue was mixed with cyclopentanone (0.16g) and tetrahydrofuran (10 mL), and samarium iodide (57 mL, 0.1 Mtetrahydrofuran solution) was added dropwise at room temperature underan argon atmosphere. The mixture was stirred at room temperature for 65hr and added to saturated aqueous ammonium chloride solution, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.026 g, 2.4%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.35 Hz, 3H) 1.30-2.03 (m,12H) 2.13-2.23 (m, 2H) 2.25-2.44 (m, 2H) 2.60-2.82 (m, 2H) 2.97-3.08 (m,2H) 3.36-3.53 (m, 3H) 4.01 (s, 2H) 4.99-5.17 (m, 1H) 7.32-7.52 (m, 6H)7.58-7.67 (m, 1H) 7.75 (dd, J=7.72, 1.32 Hz, 1H) 7.91 (s, 1H)

Reference Example 3454′-[(4-{trans-4-[(methylsulfanyl)methoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

A mixture of4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(2.0 g), dimethyl sulfoxide (30 mL) and acetic anhydride (10 mL) wasstirred at room temperature for 14 hr. The reaction mixture was added towater, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated aqueous sodium hydrogen carbonatesolution and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (1.3 g, 59%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.38 Hz, 3H) 1.38-1.89 (m,6H) 2.11-2.21 (m, 5H) 2.62-2.84 (m, 2H) 2.98-3.10 (m, 2H) 3.66-3.89 (m,1H) 4.01 (s, 2H) 4.68 (s, 2H) 4.98-5.17 (m, 1H) 7.32-7.53 (m, 6H)7.57-7.69 (m, 1H) 7.74 (d, J=7.57 Hz, 1H) 7.91 (s, 1H)

Reference Example 3464′-({4-[trans-4-(2-hydroxy-2-methylbutoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

4′-({5-Oxo-4-[trans-4-(2-oxopropoxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.094 g) was dissolved in tetrahydrofuran (1 mL), ethylmagnesiumbromide (0.12 mL, 3.0 M tetrahydrofuran solution) was added dropwise,and the mixture was stirred at room temperature for 18 hr. The reactionmixture was added to 1 M hydrochloric acid, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.060 g, 61%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.90 (t, J=7.54 Hz, 3H) 1.06 (t, J=7.35Hz, 3H) 1.13 (s, 3H) 1.36-1.59 (m, 4H) 1.65-1.86 (m, 4H) 2.08-2.28 (m,2H) 2.57-2.82 (m, 2H) 2.95-3.10 (m, 2H) 3.29 (d, J=8.85 Hz, 1H) 3.35 (d,J=8.85 Hz, 1H) 3.38-3.51 (m, 1H) 4.01 (s, 2H) 4.96-5.16 (m, 1H)7.32-7.54 (m, 6H) 7.57-7.68 (m, 1H) 7.75 (dd, J=7.72, 0.94 Hz, 1H) 7.91(s, 1H)

Reference Example 347 ethyl2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]butanoate

A mixture of4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.87 g), rhodium(II) acetate (dimer) (0.0084 g) and toluene (10 mL) washeated to 80° C. under an argon atmosphere, a solution of 2-diazobutyricacid ethyl ester (1.0 g) in toluene (10 mL) was added dropwise, and themixture was stirred at 80° C. for 30 min. The reaction mixture was addedto water, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.78 g, 71%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.88 (t, J=7.35 Hz, 3H) 0.95 (t, J=7.35 Hz,3H) 1.18-1.78 (m, 11H) 1.99-2.22 (m, 2H) 2.52-2.67 (m, 2H) 2.89-3.04 (m,2H) 3.25-3.41 (m, 1H) 3.93-4.22 (m, 5H) 4.81-5.01 (m, 1H) 7.36-7.44 (m,2H) 7.45-7.52 (m, 2H) 7.52-7.63 (m, 2H) 7.73-7.82 (m, 1H) 7.92 (dd,J=7.72, 1.13 Hz, 1H) 8.18 (s, 1H)

Reference Example 3484′-({4-[trans-4-(1-ethyl-2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

Ethyl2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]butanoate(0.20 g) was dissolved in tetrahydrofuran (2 mL), methylmagnesiumbromide (1.0 mL, 1.0 M tetrahydrofuran solution) was added dropwise at0° C., and the mixture was stirred at room temperature for 1 hr.Methylmagnesium bromide (1.0 mL, 1.0 M tetrahydrofuran solution) wasadded, and the mixture was stirred at room temperature for 2 hr. Thereaction mixture was added to 1 M hydrochloric acid, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.12 g, 65%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89-0.99 (m, 6H) 1.02 (s, 3H) 1.08 (s, 3H)1.13-1.41 (m, 4H) 1.45-1.81 (m, 4H) 2.02-2.22 (m, 2H) 2.52-2.67 (m, 2H)2.88-3.09 (m, 3H) 3.44-3.62 (m, 1H) 3.99 (s, 2H) 4.11 (s, 1H) 4.76-5.00(m, 1H) 7.35-7.44 (m, 2H) 7.46-7.51 (m, 2H) 7.53-7.63 (m, 2H) 7.72-7.82(m, 1H) 7.92 (dd, J=7.72, 0.94 Hz, 1H) 8.18 (s, 1H)

Reference Example 349 ethyl2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]butanoate

A mixture of4′-{[4-(trans-4-hydroxycyclohexyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.77 g), rhodium(II) acetate (dimer) (0.0070 g) and toluene (10 mL) washeated to 80° C. under an argon atmosphere, a solution of 2-diazobutyricacid ethyl ester (0.91 g) in toluene (10 mL) was added dropwise, and themixture was stirred at 80° C. for 30 min. The reaction mixture was addedto water, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.69 g, 73%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.88 (t, J=7.44 Hz, 3H) 0.95 (t, J=7.35 Hz,3H) 1.18-1.76 (m, 11H) 2.00-2.21 (m, 2H) 2.35 (s, 3H) 2.52-2.64 (m, 2H)2.84-2.98 (m, 2H) 3.33-3.41 (m, 1H) 3.91-4.22 (m, 5H) 4.75-4.99 (m, 1H)7.32-7.43 (m, 2H) 7.45-7.51 (m, 2H) 7.53-7.62 (m, 2H) 7.72-7.82 (m, 1H)7.92 (dd, J=7.91, 0.94 Hz, 1H)

Reference Example 3504′-({4-[trans-4-(1-ethyl-2-hydroxy-2-methylpropoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

Ethyl2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]butanoate(0.20 g) was dissolved in tetrahydrofuran (2 mL), methylmagnesiumbromide (1.0 mL, 1.0 M tetrahydrofuran solution) was added dropwise at0° C., and the mixture was stirred at room temperature for 1 hr.Methylmagnesium bromide (1.0 mL, 1.0 M tetrahydrofuran solution) wasadded, and the mixture was stirred at room temperature for 2 hr. Thereaction mixture was added to 1 M hydrochloric acid, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.11 g, 60%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.87-0.98 (m, 6H) 1.02 (s, 3H) 1.08 (s, 3H)1.12-1.37 (m, 4H) 1.46-1.75 (m, 4H) 2.02-2.19 (m, 2H) 2.36 (s, 3H)2.52-2.64 (m, 2H) 2.86-2.98 (m, 2H) 3.04 (dd, J=9.14, 2.92 Hz, 1H)3.42-3.61 (m, 1H) 3.97 (s, 2H) 4.12 (s, 1H) 4.74-4.98 (m, 1H) 7.35-7.43(m, 2H) 7.45-7.52 (m, 2H) 7.52-7.63 (m, 2H) 7.72-7.83 (m, 1H) 7.92 (dd,J=7.72, 1.13 Hz, 1H)

Reference Example 3514′-({4-[trans-4-(2-{[tert-butyl(dimethyl)silyl]oxy}-3-oxopropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-[(4-{trans-4-[(2-hydroxybut-3-en-1-yl)oxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.43 g), 2,6-lutidine (0.18 mL), tert-butyl(dimethyl)silyltrifluoromethanesulfonate (0.36 mL) and tetrahydrofuran (5 mL) wasstirred at room temperature for 24 hr. The reaction mixture was added to1 M hydrochloric acid, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated sodium hydrogen carbonateand then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure. The residueobtained by purification by silica gel column chromatography was mixedwith sodium periodate (0.85 g), acetone (10 mL), acetonitrile (10 mL),water (10 mL) and osmium tetraoxide (0.14 g, 7% immobilized catalyst),and the mixture was stirred at room temperature for 40 hr. Theprecipitate was filtered off, and the filtrate was extracted with ethylacetate. The organic layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure to give the title compound as a colorless solid (0.43g, 83%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.00 (s, 6H) 0.90 (s, 9H) 0.95 (t, J=7.35Hz, 3H) 1.19-1.37 (m, 2H) 1.47-1.79 (m, 4H) 2.01-2.22 (m, 2H) 2.52-2.68(m, 2H) 2.86-3.08 (m, 2H) 3.34-3.49 (m, 1H) 3.64-3.76 (m, 2H) 3.99 (s,2H) 4.33 (t, J=4.62 Hz, 1H) 4.76-5.03 (m, 1H) 7.36-7.44 (m, 2H)7.45-7.51 (m, 2H) 7.53-7.63 (m, 2H) 7.71-7.84 (m, 1H) 7.93 (dd, J=7.72,0.94 Hz, 1H) 8.18 (s, 1H) 9.58 (s, 1H)

Reference Example 3524′-({4-[trans-4-(2-{[tert-butyl(dimethyl)silyl]oxy}-3,3-difluoropropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

4′-({4-[trans-4-(2-{[tert-Butyl(dimethyl)silyl]oxy}-3-oxopropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(batch 1: 0.37 g, batch 2: 0.050 g) was dissolved in toluene (batch 1: 4mL, batch 2: 1 mL), N,N-diethylaminosulfur trifluoride (batch 1: 0.28 g,batch 2: 0.037 g) was added at room temperature, and the mixture wasstirred at room temperature (batch 1: 1.5 hr, batch 2: 3 hr). Thereaction mixtures of batch 1 and batch 2 were combined, saturatedaqueous sodium hydrogen carbonate solution was gradually added, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.30 g, 67%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.09 (d, J=6.44 Hz, 6H) 0.88 (s, 9H) 0.95(t, J=7.19 Hz, 3H) 1.20-1.42 (m, 2H) 1.48-1.84 (m, 4H) 2.01-2.21 (m, 2H)2.53-2.70 (m, 2H) 2.90-3.05 (m, 2H) 3.34-3.43 (m, 1H) 3.44-3.64 (m, 2H)3.89-4.01 (m, 3H) 4.75-5.04 (m, 1H) 5.93 (dt, J=55.09, 3.41 Hz, 1H)7.34-7.45 (m, 2H) 7.45-7.52 (m, 2H) 7.53-7.64 (m, 2H) 7.72-7.84 (m, 1H)7.93 (d, J=7.57 Hz, 1H) 8.19 (s, 1H)

Reference Example 353 ethyl[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate

A mixture of4′-{[4-(trans-4-hydroxycyclohexyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(1.5 g), rhodium(II) acetate (dimer) (0.0070 g) and toluene (15 mL) washeated to 80° C. under an argon atmosphere, a solution of ethyl2-diazoacetate (1.6 g) in toluene (15 mL) was added dropwise, and themixture was stirred at 80° C. for 10 min. The reaction mixture was addedto water, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (1.0 g, 56%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.19 Hz, 3H) 1.21 (t, J=7.19 Hz,3H) 1.24-1.40 (m, 2H) 1.47-1.81 (m, 4H) 2.09-2.20 (m, 2H) 2.35 (s, 3H)2.51-2.66 (m, 2H) 2.85-2.98 (m, 2H) 3.34-3.48 (m, 1H) 3.97 (s, 2H)4.06-4.18 (m, 4H) 4.77-4.99 (m, 1H) 7.36-7.43 (m, 2H) 7.45-7.51 (m, 2H)7.52-7.62 (m, 2H) 7.70-7.83 (m, 1H) 7.93 (d, J=7.57 Hz, 1H)

Reference Example 3544′-[(2-methyl-4-{trans-4-[(2-methyloxiran-2-yl)methoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

2-[(trans-4-{6-[(2′-Cyanobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide(0.45 g) was dissolved in tetrahydrofuran (5 mL), methylmagnesiumbromide (2.3 mL, 1.0 M tetrahydrofuran solution) was added dropwise, andthe mixture was stirred at room temperature for 4 hr. The reactionmixture was added to 1 M hydrochloric acid, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, the residue was added to amixture of trimethylsulfoxonium iodide (0.20 g), sodium hydride (0.038g) and dimethyl sulfoxide (5 mL) stirred at room temperature for 1 hr inadvance, and the mixture was stirred at room temperature for 16 hr. Thereaction mixture was added to water, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.19 g,46%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.25 Hz, 3H) 1.20-1.38 (m, 5H)1.48-1.77 (m, 4H) 2.03-2.18 (m, 2H) 2.36 (s, 3H) 2.52-2.68 (m, 4H)2.86-2.98 (m, 2H) 3.33-3.42 (m, 2H) 3.56 (d, J=11.30 Hz, 1H) 3.97 (s,2H) 4.68-4.99 (m, 1H) 7.33-7.44 (m, 2H) 7.45-7.52 (m, 2H) 7.52-7.63 (m,2H) 7.71-7.83 (m, 1H) 7.92 (dd, J=7.72, 0.94 Hz, 1H)

Reference Example 3554′-({4-[trans-4-(3-fluoro-2-hydroxy-2-methylpropoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-[(2-methyl-4-{trans-4-[(2-methyloxiran-2-yl)methoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.19 g), tetra-n-butylammonium dihydrogentrifluoride (0.65 g) andchlorobenzene (0.5 mL) was stirred at 120° C. for 20 hr. The reactionmixture was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.094 g, 46%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.25 Hz, 3H) 1.06 (d, J=2.07 Hz,3H) 1.19-1.41 (m, 2H) 1.50-1.78 (m, 4H) 2.03-2.17 (m, 2H) 2.36 (s, 3H)2.52-2.67 (m, 2H) 2.82-2.98 (m, 2H) 3.21-3.43 (m, 3H) 3.97 (s, 2H) 4.19(d, J=47.85 Hz, 2H) 4.78 (s, 1H) 4.80-4.96 (m, 1H) 7.34-7.42 (m, 2H)7.45-7.52 (m, 2H) 7.52-7.64 (m, 2H) 7.73-7.83 (m, 1H) 7.92 (dd, J=7.72,0.94 Hz, 1H)

Reference Example 356 ethyl2-[(trans-4-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]butanoate

A mixture of3′-fluoro-4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.50 g), rhodium(II) acetate (dimer) (0.0050 g) and toluene (5 mL) washeated to 80° C. under an argon atmosphere, a solution of 2-diazobutyricacid ethyl ester (0.87 g) in toluene (5 mL) was added dropwise, and themixture was stirred at 80° C. for 10 min. The reaction mixture wasconcentrated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.35 g, 56%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.88 (t, J=7.38 Hz, 3H) 0.95 (t, J=7.38 Hz,3H) 1.13-1.79 (m, 11H) 1.87-2.22 (m, 2H) 2.52-3.03 (m, 4H) 3.25-3.38 (m,1H) 3.81-4.25 (m, 5H) 4.75-4.98 (m, 1H) 7.21-7.39 (m, 2H) 7.46 (dd,J=11.17, 1.70 Hz, 1H) 7.54-7.67 (m, 2H) 7.75-7.84 (m, 1H) 7.91-7.99 (m,1H) 8.19 (s, 1H)

Reference Example 3574′-({4-[trans-4-(1-ethyl-2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)-3′-fluorobiphenyl-2-carbonitrile

Ethyl2-[(trans-4-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]butanoate(0.35 g) was dissolved in tetrahydrofuran (4 mL), methylmagnesiumbromide (1.7 mL, 1.0 M tetrahydrofuran solution) was added dropwise at0° C., and the mixture was stirred at room temperature for 3 hr.Methylmagnesium bromide (3.5 mL, 1.0 M tetrahydrofuran solution) wasadded, and the mixture was stirred at room temperature for 1 hr. Thereaction mixture was added to 1 M hydrochloric acid, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.20 g, 60%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89-0.99 (m, 6H) 1.01 (s, 3H) 1.08 (s, 3H)1.13-1.81 (m, 8H) 2.01-2.21 (m, 2H) 2.52-2.66 (m, 2H) 2.87-3.09 (m, 3H)3.44-3.62 (m, 1H) 3.97 (s, 2H) 4.11 (s, 1H) 4.77-5.00 (m, 1H) 7.25-7.40(m, 2H) 7.46 (dd, J=10.98, 1.51 Hz, 1H) 7.55-7.70 (m, 2H) 7.75-7.86 (m,1H) 7.90-8.02 (m, 1H) 8.20 (s, 1H)

Reference Example 3584′-[(2-methyl-4-{trans-4-[(methylsulfanyl)methoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

A mixture of4′-{[4-(trans-4-hydroxycyclohexyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(1.5 g), dimethyl sulfoxide (45 mL) and acetic anhydride (15 mL) wasstirred at room temperature for 17 hr. The reaction mixture was added towater, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated aqueous sodium hydrogen carbonatesolution and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.83 g, 49%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.35 Hz, 3H) 1.22-1.45 (m, 2H)1.50-1.81 (m, 4H) 2.02-2.15 (m, 5H) 2.37 (s, 3H) 2.52-2.72 (m, 2H)2.82-3.04 (m, 2H) 3.53-3.73 (m, 1H) 3.97 (s, 2H) 4.69 (s, 2H) 4.80-5.06(m, 1H) 7.34-7.44 (m, 2H) 7.45-7.52 (m, 2H) 7.53-7.66 (m, 2H) 7.72-7.85(m, 1H) 7.92 (dd, J=7.91, 1.13 Hz, 1H)

Reference Example 3594′-[(4-{trans-4-[(1-hydroxycyclobutyl)methoxy]cyclohexyl}-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

4′-[(2-Methyl-4-{trans-4-[(methylsulfanyl)methoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(1.3 g) was dissolved in toluene (10 mL), and sulfuryl chloride (0.20mL) was added at 0° C. The mixture was stirred at room temperature for 1hr, the precipitate was filtrated off, and the filtrate was concentratedunder reduced pressure. The residue was mixed with cyclobutanone (1.7 g)and tetrahydrofuran (5 mL), and samarium iodide (48 mL, 0.1 Mtetrahydrofuran solution) was added dropwise at room temperature underan argon atmosphere. The mixture was stirred at room temperature for 18hr. The reaction mixture was added to saturated aqueous ammoniumchloride solution, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.098 g, 7.1%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.19 Hz, 3H) 1.19-2.22 (m, 14H)2.36 (s, 3H) 2.54-2.69 (m, 2H) 2.84-3.03 (m, 2 H) 3.33-3.43 (m, 3H) 3.97(s, 2H) 4.73-4.98 (m, 2H) 7.34-7.44 (m, 2H) 7.45-7.52 (m, 2H) 7.53-7.65(m, 2H) 7.71-7.82 (m, 1H) 7.93 (d, J=7.19 Hz, 1H)

Reference Example 3603′-fluoro-4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

Ethyl[(trans-4-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate(0.60 g) was dissolved in tetrahydrofuran (6 mL), methylmagnesiumbromide (3.0 mL, 1.0 M tetrahydrofuran solution) was added dropwise at0° C., and the mixture was stirred at 0° C. for 1 hr and then at roomtemperature for 16 hr. The reaction mixture was added to 1 Mhydrochloric acid, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.39 g, 66%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.19 Hz, 3H) 1.06 (s, 6H)1.21-1.38 (m, 2H) 1.46-1.77 (m, 4H) 2.03-2.17 (m, 2H) 2.37 (s, 3H)2.51-2.65 (m, 2H) 2.82-2.98 (m, 2H) 3.19 (s, 2H) 3.24-3.38 (m, 1H) 3.94(s, 2H) 4.22 (s, 1H) 4.66-5.01 (m, 1H) 7.23-7.38 (m, 2H) 7.45 (d, J=9.47Hz, 1H) 7.54-7.69 (m, 2H) 7.73-7.85 (m, 1H) 7.95 (d, J=7.95 Hz, 1H)

Reference Example 361 ethyl2-[(trans-4-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]pent-4-enoate

A mixture of3′-fluoro-4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(2.0 g), rhodium(II) acetate (dimer) (0.018 g) and toluene (20 mL) washeated to 80° C. under an argon atmosphere, a solution of ethyl2-diazopent-4-enoate (3.8 g) in toluene (20 mL) was added dropwise, andthe mixture was stirred at 80° C. for 10 min. A solution of ethyl2-diazopent-4-enoate (3.8 g) in toluene (10 mL) was further added, andthe mixture was stirred at 80° C. for 10 min. The reaction mixture wasconcentrated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.81 g, 32%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.35 Hz, 3H) 1.13-1.77 (m, 9H)1.87-2.19 (m, 2H) 2.26-2.48 (m, 2H) 2.53-3.06 (m, 4H) 3.33-3.43 (m, 1H)3.97 (s, 2H) 4.07-4.22 (m, 3H) 4.78-4.97 (m, 1H) 4.99-5.24 (m, 2H)5.66-5.88 (m, 1H) 7.25-7.40 (m, 2H) 7.41-7.51 (m, 1H) 7.54-7.68 (m, 2 H)7.74-7.87 (m, 1H) 7.95 (dd, J=7.82, 1.04 Hz, 1H) 8.19 (s, 1H)

Reference Example 362 ethyl2-[(trans-4-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-4-hydroxybutanoate

A mixture of ethyl2-[(trans-4-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]pent-4-enoate(0.81 g), sodium periodate (1.4 g), acetone (20 mL), acetonitrile (20mL), water (20 mL) and osmium tetraoxide (0.24 g, 7% immobilizedcatalyst) was stirred at room temperature for 14 hr. The precipitate wasfiltered off, and the filtrate was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was dissolved in tetrahydrofuran (5 mL) and methanol (10mL). Sodium tetrahydroborate (0.084 g) was added at 0° C., and themixture was stirred at 0° C. for 3 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture. After evaporationof the solvent under reduced pressure, the residue was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.29 g,36%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.35 Hz, 3H) 1.21 (t, J=7.06 Hz,3H) 1.25-1.89 (m, 8H) 1.95-2.20 (m, 2H) 2.52-2.65 (m, 2H) 2.90-3.05 (m,2H) 3.26-3.41 (m, 1H) 3.42-3.56 (m, 2H) 3.97 (s, 2H) 4.06-4.23 (m, 3H)4.52 (t, J=5.09 Hz, 1H) 4.77-4.99 (m, 1H) 7.25-7.40 (m, 2H) 7.46 (dd,J=11.11, 1.70 Hz, 1H) 7.55-7.69 (m, 2H) 7.73-7.86 (m, 1H) 7.95 (dd,J=7.72, 0.94 Hz, 1H) 8.19 (s, 1H)

Reference Example 363 ethyl2-[(trans-4-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-4-{[(4-methylphenyl)sulfonyl]oxy}butanoate

A mixture of ethyl2-[(trans-4-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-4-hydroxybutanoate(0.47 g), 4-methylbenzenesulfonyl chloride (0.59 g) and pyridine (5 mL)was stirred at room temperature for 3 hr. The reaction mixture was addedto 1 M hydrochloric acid, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.42 g,70%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.38 Hz, 3H) 1.14-2.05 (m, 13H)2.39 (s, 3H) 2.42-2.59 (m, 2H) 2.89-3.03 (m, 2H) 3.19-3.31 (m, 1H) 3.98(s, 2H) 4.03-4.18 (m, 5H) 4.70-4.91 (m, 1H) 7.25-7.41 (m, 2H) 7.42-7.55(m, 3H) 7.55-7.67 (m, 2H) 7.74-7.85 (m, 3H) 7.95 (d, J=7.95 Hz, 1H) 8.21(s, 1H)

Reference Example 364 ethyl1-[(trans-4-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]cyclopropanecarboxylate

A mixture of ethyl2-[(trans-4-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-4-{[(4-methylphenyl)sulfonyl]oxy}butanoate(0.42 g), potassium tert-butoxide (0.24 g) and tetrahydrofuran (5 mL)was stirred at 0° C. for 10 min. The reaction mixture was added to 1 Mhydrochloric acid, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.051 g, 15%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.07 (t, J=7.25 Hz, 3H) 1.14-1.88 (m,13H) 2.17-2.32 (m, 2H) 2.59-2.82 (m, 2H) 2.98-3.11 (m, 2H) 3.56-3.78 (m,1H) 4.02 (s, 2H) 4.19 (q, J=7.16 Hz, 2H) 4.87-5.16 (m, 1H) 7.21-7.52 (m,5H) 7.59-7.69 (m, 1H) 7.76 (d, J=7.72 Hz, 1H) 7.91 (s, 1H)

Reference Example 3653′-fluoro-4′-{[4-(trans-4-{[1-(1-hydroxy-1-methylethyl)cyclopropyl]oxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

Ethyl1-[(trans-4-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]cyclopropanecarboxylate(0.051 g) was dissolved in tetrahydrofuran (1 mL), methylmagnesiumbromide (0.25 mL, 1.0 M tetrahydrofuran solution) was added dropwise at0° C., and the mixture was stirred at 0° C. for 30 min and then at roomtemperature for 30 min. Methylmagnesium bromide (1.0 mL, 1.0 Mtetrahydrofuran solution) was added, and the mixture was stirred at roomtemperature for 10 min. Methylmagnesium bromide (1.0 mL, 1.0 Mtetrahydrofuran solution) was added, and the mixture was stirred at roomtemperature for 10 min. Methylmagnesium bromide (1.0 mL, 1.0 Mtetrahydrofuran solution) was added, and the mixture was stirred at roomtemperature for 10 min. The reaction mixture was added to 1 Mhydrochloric acid, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.032 g, 65%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.64-0.91 (m, 4H) 1.06 (t, J=7.35 Hz,3H) 1.23 (s, 6H) 1.39-1.55 (m, 2H) 1.64-1.86 (m, 4H) 2.06-2.14 (m, 2H)2.58-2.82 (m, 2H) 2.96-3.12 (m, 2H) 3.49-3.70 (m, 1H) 4.01 (s, 2H)4.90-5.14 (m, 1H) 7.19-7.30 (m, 2H) 7.30-7.55 (m, 3H) 7.59-7.69 (m, 1H)7.72-7.82 (m, 1H) 7.92 (s, 1H)

Reference Example 366 ethyl2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]pent-4-enoate

A mixture of4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(1.8 g), rhodium(II) acetate (dimer) (0.018 g) and toluene (20 mL) washeated to 80° C. under an argon atmosphere, a solution of ethyl2-diazopent-4-enoate (3.7 g) in toluene (20 mL) was added dropwise, andthe mixture was stirred at 80° C. for 10 min. A solution of ethyl2-diazopent-4-enoate (3.7 g) in toluene (10 mL) was further added, andthe mixture was stirred at 80° C. for 10 min. The reaction mixture wasconcentrated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.98 g, 41%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.38 Hz, 3H) 1.21 (t, J=7.00 Hz,3H) 1.27-1.76 (m, 6H) 1.90-2.18 (m, 2H) 2.26-2.48 (m, 2H) 2.52-3.04 (m,4H) 3.32-3.43 (m, 1H) 3.99 (s, 2H) 4.05-4.22 (m, 3H) 4.83-4.98 (m, 1H)5.02-5.25 (m, 2H) 5.66-5.87 (m, 1H) 7.35-7.44 (m, 2H) 7.45-7.52 (m, 2H)7.53-7.63 (m, 2H) 7.71-7.83 (m, 1H) 7.89-7.98 (m, 1H) 8.18 (s, 1H)

Reference Example 367 ethyl2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-4-hydroxybutanoate

A mixture of ethyl2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]pent-4-enoate(0.98 g), sodium periodate (1.7 g), acetone (20 mL), acetonitrile (20mL), water (20 mL) and osmium tetraoxide (0.30 g, 7% immobilizedcatalyst) was stirred at room temperature for 14 hr. The precipitate wasfiltered off, and the filtrate was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was dissolved in tetrahydrofuran (5 mL) and methanol (10mL), sodium tetrahydroborate (0.10 g) was added at 0° C., and themixture was stirred at 0° C. for 2 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture. After evaporationof the solvent under reduced pressure, the residue was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.37 g,37%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.38 Hz, 3H) 1.21 (t, J=7.19 Hz,3H) 1.25-1.88 (m, 8H) 1.99-2.21 (m, 2H) 2.52-2.66 (m, 2H) 2.90-3.04 (m,2H) 3.29-3.41 (m, 1H) 3.43-3.54 (m, 2H) 3.99 (s, 2H) 4.06-4.21 (m, 3H)4.53 (t, J=5.30 Hz, 1H) 4.79-5.03 (m, 1H) 7.36-7.44 (m, 2H) 7.45-7.52(m, 2H) 7.52-7.64 (m, 2H) 7.73-7.83 (m, 1H) 7.88-8.00 (m, 1H) 8.18 (s,1H)

Reference Example 368 ethyl2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-4-{[(4-methylphenyl)sulfonyl]oxy}butanoate

A mixture of ethyl2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-4-hydroxybutanoate(0.54 g), 4-methylbenzenesulfonyl chloride (0.70 g) and pyridine (6 mL)was stirred at room temperature for 75 min. The reaction mixture wasadded to 1 M hydrochloric acid, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.45 g,65%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.19 Hz, 3H) 1.15-1.35 (m, 5H)1.47-1.73 (m, 4H) 1.74-1.89 (m, 2H) 1.90-2.07 (m, 2H) 2.40 (s, 3H)2.43-2.61 (m, 2H) 2.90-3.06 (m, 2H) 3.20-3.31 (m, 1H) 3.95-4.19 (m, 7H)4.64-4.99 (m, 1H) 7.32-7.65 (m, 8H) 7.71-7.88 (m, 3H) 7.93 (d, J=7.95Hz, 1H) 8.19 (s, 1H)

Reference Example 369 ethyl1-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]cyclopropanecarboxylate

A mixture of ethyl2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-4-{[(4-methylphenyl)sulfonyl]oxy}butanoate(0.45 g), potassium tert-butoxide (0.26 g) and tetrahydrofuran (20 mL)was stirred at −10° C. for 10 min. The reaction mixture was added to 1 Mhydrochloric acid, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.19 g, 55%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.38 Hz, 3H) 1.06-1.80 (m, 13H)2.02-2.22 (m, 2H) 2.51-2.68 (m, 2H) 2.87-3.04 (m, 2H) 3.48-3.71 (m, 1H)3.99 (s, 2H) 4.11 (q, J=7.07 Hz, 2H) 4.68-5.03 (m, 1H) 7.36-7.45 (m, 2H)7.45-7.51 (m, 2H) 7.52-7.64 (m, 2H) 7.71-7.82 (m, 1H) 7.93 (d, J=7.95Hz, 1H) 8.18 (s, 1H)

Reference Example 3704′-{[4-(trans-4-{[1-(1-hydroxy-1-methylethyl)cyclopropyl]oxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

Ethyl1-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]cyclopropanecarboxylate(0.19 g) was dissolved in tetrahydrofuran (2 mL), methylmagnesiumbromide (3.3 mL, 1.0 M tetrahydrofuran solution) was added dropwise at0° C., and the mixture was stirred at room temperature for 30 min.Methylmagnesium bromide (3.3 mL, 1.0 M tetrahydrofuran solution) wasadded, and the mixture was stirred at room temperature for 10 min.Methylmagnesium bromide (3.3 mL, 1.0 M tetrahydrofuran solution) wasadded, and the mixture was stirred at room temperature for 10 min. Thereaction mixture was added to 1 M hydrochloric acid, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.049 g, 26%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.55-0.67 (m, 2H) 0.68-0.77 (m, 2H) 0.94 (t,J=7.35 Hz, 3H) 1.14 (s, 6H) 1.21-1.39 (m, 2H) 1.45-1.73 (m, 4H)1.96-2.07 (m, 2H) 2.53-2.67 (m, 2H) 2.90-3.04 (m, 2H) 3.44-3.62 (m, 1H)3.99 (s, 2H) 4.20 (s, 1H) 4.74-4.97 (m, 1H) 7.32-7.64 (m, 6H) 7.72-7.81(m, 1H) 7.90-7.97 (m, 1H) 8.18 (s, 1H)

Reference Example 371 ethyl2-[(trans-4-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]propanoate

A mixture of3′-fluoro-4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(3.0 g), rhodium(II) acetate (dimer) (0.027 g) and toluene (30 mL) washeated to 80° C. under an argon atmosphere, a solution of ethyl2-diazopropionate (3.2 g) in toluene (30 mL) was added dropwise, and themixture was stirred at 80° C. for 10 min. A solution of ethyl2-diazopropionate (1.6 g) in toluene (10 mL) was added, and the mixturewas stirred at 80° C. for 10 min. The reaction mixture was concentratedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography to give the title compound as a colorless solid(3.2 g, 88%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.38 Hz, 3H) 1.13-1.76 (m, 12H)1.88-2.18 (m, 2H) 2.52-2.64 (m, 2H) 2.91-3.04 (m, 2H) 3.33-3.43 (m, 1H)3.97 (s, 2H) 4.06-4.23 (m, 3H) 4.79-4.96 (m, 1H) 7.25-7.40 (m, 2H)7.42-7.49 (m, 1H) 7.56-7.67 (m, 2H) 7.74-7.86 (m, 1H) 7.92-8.00 (m, 1H)8.19 (s, 1H)

Reference Example 3723′-fluoro-4′-({4-[trans-4-(2-hydroxy-1-methylethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of ethyl2-[(trans-4-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]propanoate(1.5 g), lithium tetrahydroborate (0.18 g) and tetrahydrofuran (15 mL)was stirred at 0° C. for 1 hr and then at room temperature for 6 hr.Lithium tetrahydroborate (0.18 g) was further added, and the mixture wasstirred at room temperature for 15 hr. The reaction mixture was added tosaturated aqueous ammonium chloride solution, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.81 g, 58%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.35 Hz, 3H) 1.03 (d, J=6.22 Hz,3H) 1.22-1.41 (m, 2H) 1.52-1.76 (m, 4H) 1.99-2.14 (m, 2H) 2.52-2.68 (m,2H) 2.86-3.05 (m, 2H) 3.17-3.60 (m, 4H) 3.97 (s, 2H) 4.75-4.98 (m, 1H)7.24-7.68 (m, 5H) 7.70-7.88 (m, 1H) 7.95 (dd, J=7.72, 0.94 Hz, 1H) 8.20(s, 1H)

Reference Example 3733′-fluoro-4′-({4-[trans-4-(1-oxiran-2-ylethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of3′-fluoro-4′-({4-[trans-4-(2-hydroxy-1-methylethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.81 g), Dess-Martin periodinane (1.2 g) and acetonitrile (10 mL) wasstirred at room temperature for 2 hr. Saturated aqueous sodium hydrogencarbonate solution and aqueous sodium thiosulfate solution were added tothe reaction mixture. After evaporation of the solvent under reducedpressure, the residue was extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,the residue was added to a mixture of trimethylsulfoxonium iodide (0.39g), sodium hydride (0.072 g) and dimethyl sulfoxide (10 mL) stirred atroom temperature for 1 hr in advance, and the mixture was stirred atroom temperature for 15 hr. The reaction mixture was added to water, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.15 g, 18%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.73-1.01 (m, 3H) 1.06-1.80 (m, 9H)1.92-2.14 (m, 2H) 2.20-3.11 (m, 6H) 3.18-3.69 (m, 3H) 3.97 (s, 2H)4.23-5.16 (m, 1H) 7.20-7.51 (m, 3H) 7.53-7.70 (m, 2H) 7.74-7.83 (m, 1H)7.86 (s, 0.33H) 7.95 (dd, J=7.72, 0.94 Hz, 1H) 8.20 (s, 0.67H)

Reference Example 3743′-fluoro-4′-({4-[trans-4-(3-fluoro-2-hydroxy-1-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of3′-fluoro-4′-({4-[trans-4-(1-oxiran-2-ylethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.15 g), tetra-n-butylammonium dihydrogentrifluoride (0.49 g) andchlorobenzene (0.5 mL) was stirred at 120° C. for 24 hr and then at roomtemperature for 40 hr. The reaction mixture was concentrated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.081 g,51%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.92-1.12 (m, 3H) 1.16-1.54 (m, 6H)1.60-1.89 (m, 3H) 1.99-2.30 (m, 2H) 2.42-3.12 (m, 4H) 3.39-3.78 (m, 3H)4.02 (s, 2H) 4.29-4.67 (m, 2H) 4.98-5.18 (m, 1H) 7.22-7.55 (m, 6H)7.60-7.72 (m, 1H) 7.73-7.83 (m, 1H) 7.92 (s, 1H)

Reference Example 3753′-fluoro-4′-{[4-(trans-4-{1-[2-(fluoromethyl)oxiran-2-yl]ethoxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of3′-fluoro-4′-({4-[trans-4-(3-fluoro-2-hydroxy-1-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.15 g), Dess-Martin periodinane (0.22 g) and acetonitrile (2 mL) wasstirred at room temperature for 12 hr. Saturated aqueous sodium hydrogencarbonate solution and aqueous sodium thiosulfate solution were added tothe reaction mixture, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, the residue was added to a mixture of trimethylsulfoxoniumiodide (0.057 g), sodium hydride (0.010 g) and dimethyl sulfoxide (4 mL)stirred at room temperature for 1 hr in advance, and the mixture wasstirred at room temperature for 1 hr. The reaction mixture was added towater, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.079 g, 52%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.35 Hz, 3H) 1.04-1.84 (m, 9H)2.00-2.15 (m, 2H) 2.52-3.04 (m, 6H) 3.34-3.76 (m, 2H) 3.97 (s, 2H)4.43-4.74 (m, 2H) 4.77-5.00 (m, 1H) 7.12-7.53 (m, 3H) 7.54-7.69 (m, 2H)7.72-7.88 (m, 1H) 7.95 (dd, J=7.72, 0.94 Hz, 1H) 8.20 (s, 1H)

Reference Example 376 ethyl3-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclobutanecarboxylate

A mixture of ethyl 3-(4H-1,2,4-triazol-3-ylamino)cyclobutanecarboxylate(4.0 g), ethyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate(12 g) and N,N-diethylaniline (15 mL) was stirred at 180° C. for 48 hrand then at room temperature for 38 hr. The reaction mixture was addedto 1 M hydrochloric acid, and the mixture was extracted with ethylacetate. The organic layer was washed with 1 M hydrochloric acid andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (4.0 g, 41%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.38 Hz, 3H) 1.11-1.27 (m, 3H)1.44-1.77 (m, 2H) 2.36-3.48 (m, 7H) 3.87-4.24 (m, 4H) 5.06-5.85 (m, 1H)7.17-7.53 (m, 3H) 7.54-7.73 (m, 2H) 7.74-7.85 (m, 1H) 7.90-8.01 (m, 1H)8.13-8.30 (m, 1H)

Reference Example 3774′-{[4-(3-acetylcyclobutyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile

A mixture of ethyl3-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclobutanecarboxylate(4.0 g), tetrahydrofuran (40 mL), ethanol (40 mL) and 1 M aqueous sodiumhydroxide solution (40 mL) was stirred at room temperature for 2 hr. Thereaction mixture was neutralized with 1 M hydrochloric acid. Afterevaporation of the solvent under reduced pressure, the residue wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, the residue was mixed withN,O-dimethylhydroxyamine hydrochloride (1.1 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.2 g),1-hydroxybenzotriazole (1.6 g), triethylamine (3.3 mL) andN,N-dimethylformaldehyde (40 mL), and the mixture was stirred at roomtemperature for 14 hr. The reaction mixture was added to 1 Mhydrochloric acid, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The residue obtained by purification by silica gel column chromatographywas dissolved in tetrahydrofuran (40 mL), methylmagnesium bromide (23mL, 1.0 M tetrahydrofuran solution) was added dropwise at 0° C., and themixture was stirred at 0° C. for 2 hr. Methylmagnesium bromide (11 mL,1.0 M tetrahydrofuran solution) was added, and the mixture was stirredat room temperature for 30 min. The reaction mixture was added to 1 Mhydrochloric acid, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (2.8 g, 73%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.38 Hz, 3H) 1.46-1.77 (m, 2H)2.07-2.20 (m, 3H) 2.37-2.48 (m, 2H) 2.85-3.57 (m, 5H) 3.96 (s, 2H)5.16-5.64 (m, 1H) 7.20-7.53 (m, 3H) 7.54-7.70 (m, 2H) 7.74-7.85 (m, 1H)7.95 (d, J=7.95 Hz, 1H) 8.13-8.31 (m, 1H)

Reference Example 3783′-fluoro-4′-{[4-(cis-3-hydroxycyclobutyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

To a mixture of4′-{[4-(3-acetylcyclobutyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile(2.8 g), 30% hydrogen peroxide (48 mL) and chloroform (50 mL) wasgradually added dropwise trifluoroacetic acid anhydride (32 mL), and themixture was heated under reflux for 15 hr. Saturated aqueous sodiumhydrogen carbonate solution and aqueous sodium thiosulfate solution weregradually added to the reaction mixture, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated brine,and dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure, the residue was mixed with tetrahydrofuran (30mL), methanol (30 mL) and 1 M aqueous sodium hydroxide solution (30 mL),and the mixture was stirred at room temperature for 1 hr. The reactionmixture was neutralized with 1 M hydrochloric acid. After evaporation ofthe solvent under reduced pressure, the residue was extracted with ethylacetate. The organic layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The residue obtained by purification by silica gelcolumn chromatography was mixed with Dess-Martin periodinane (2.8 g) andacetonitrile (15 mL), and the mixture was stirred at room temperaturefor 2 hr. Saturated aqueous sodium hydrogen carbonate solution andaqueous sodium thiosulfate solution were added to the reaction mixture.After evaporation of the solvent under reduced pressure, the residue wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. 33% of the residue was dissolvedin tetrahydrofuran (3 mL) and methanol (5 mL), sodium tetrahydroborate(0.094 g) was added at 0° C., and the mixture was stirred at roomtemperature for 14 hr. Saturated aqueous ammonium chloride solution wasadded to the reaction mixture, the solvent was evaporated under reducedpressure, and the residue was extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.67 g, 75%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.19 Hz, 3H) 1.48-1.73 (m, 2H)2.52-2.63 (m, 2H) 2.82-3.06 (m, 4H) 3.82-3.98 (m, 3H) 4.69-4.92 (m, 1H)5.21 (d, J=5.68 Hz, 1H) 7.19-7.51 (m, 3H) 7.53-7.68 (m, 2H) 7.73-7.84(m, 1H) 7.95 (d, J=7.57 Hz, 1H) 8.22 (s, 1H)

Reference Example 379 ethyl[(cis-3-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclobutyl)oxy]acetate

A mixture of3′-fluoro-4′-{[4-(cis-3-hydroxycyclobutyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.67 g), rhodium(II) acetate (dimer) (0.0066 g) and toluene (10 mL) washeated to 80° C. under an argon atmosphere, a solution of ethyldiazoacetate (1.5 g) in toluene (10 mL) was added dropwise, and themixture was stirred at 80° C. for 10 min. The reaction mixture wasconcentrated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.29 g, 37%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.38 Hz, 3H) 1.20 (t, J=7.38 Hz,3H) 1.52-1.75 (m, 2H) 2.52-2.67 (m, 2H) 2.86-3.26 (m, 4H) 3.82-3.99 (m,3H) 4.07-4.20 (m, 4H) 4.79-5.08 (m, 1H) 7.18-7.51 (m, 3H) 7.54-7.71 (m,2H) 7.73-7.86 (m, 1H) 7.95 (d, J=7.57 Hz, 1H) 8.23 (s, 1H)

Reference Example 3803′-fluoro-4′-({4-[cis-3-(2-hydroxy-2-methylpropoxy)cyclobutyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

Ethyl[(cis-3-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclobutyl)oxy]acetate(0.29 g) was dissolved in tetrahydrofuran (3 mL), methylmagnesiumbromide (1.6 mL, 1.0 M tetrahydrofuran solution) was added dropwise at0° C., and the mixture was stirred at room temperature for 1 hr. Thereaction mixture was added to 1 M hydrochloric acid, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.17 g, 60%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.38 Hz, 3H) 1.08 (s, 6H)1.49-1.73 (m, 2H) 2.53-2.71 (m, 2H) 2.87-3.07 (m, 4H) 3.11 (s, 2H)3.73-3.87 (m, 1H) 3.96 (s, 2H) 4.29 (s, 1H) 4.70-5.03 (m, 1H) 7.22-7.51(m, 3H) 7.54-7.68 (m, 2H) 7.73-7.84 (m, 1H) 7.95 (d, J=7.57 Hz, 1H) 8.22(s, 1H)

Reference Example 381 ethyltrans-3-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclobutanecarboxylate

A mixture of ethyl 3-(4H-1,2,4-triazol-3-ylamino)cyclobutanecarboxylate(2.5 g), ethyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate(7.9 g) and N,N-diethylaniline (10 mL) was stirred at 180° C. for 18 hr.The reaction mixture was added to 1 M hydrochloric acid, and the mixturewas extracted with ethyl acetate. The organic layer was washed with 1 Mhydrochloric acid and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.86 g,14%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.19 Hz, 3H) 1.18-1.27 (m, 3H)1.28-1.73 (m, 2H) 2.17-3.46 (m, 7H) 3.97 (s, 2H) 4.14 (q, J=7.07 Hz, 2H)5.50-5.77 (m, 1H) 7.22-7.51 (m, 3H) 7.53-7.71 (m, 2H) 7.73-7.85 (m, 1H)7.95 (d, J=7.57 Hz, 1H) 8.24 (s, 1H)

Reference Example 3824′-{[4-(trans-3-acetylcyclobutyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile

A mixture of ethyltrans-3-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclobutanecarboxylate(0.86 g), tetrahydrofuran (10 mL), ethanol (10 mL) and 1 M aqueoussodium hydroxide solution (10 mL) was stirred at room temperature for 2hr. The reaction mixture was neutralized with 1 M hydrochloric acid.After evaporation of the solvent under reduced pressure, the residue wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, the residue was mixed withN,O-dimethylhydroxyamine hydrochloride (0.24 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.48 g),1-hydroxybenzotriazole (0.33 g), triethylamine (0.69 mL) andN,N-dimethylformaldehyde (10 mL), and the mixture was stirred at roomtemperature for 14 hr. The reaction mixture was added to 1 Mhydrochloric acid, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The residue obtained by silica gel column chromatography was dissolvedin tetrahydrofuran (10 mL), methylmagnesium bromide (6.6 mL, 1.0 Mtetrahydrofuran solution) was added dropwise at 0° C., and the mixturewas stirred at 0° C. for 1 hr. The reaction mixture was added to 1 Mhydrochloric acid, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.49 g, 60%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.38 Hz, 3H) 1.40-1.82 (m, 2H)2.15 (s, 3H) 2.38-2.48 (m, 2H) 2.83-3.05 (m, 2H) 3.12-3.28 (m, 2H)3.34-3.56 (m, 1H) 3.96 (s, 2H) 5.10-5.60 (m, 1H) 7.15-7.51 (m, 3H)7.51-7.67 (m, 2H) 7.71-7.86 (m, 1H) 7.95 (d, J=7.57 Hz, 1H) 8.24 (s, 1H)

Reference Example 3833′-fluoro-4′-{[4-(trans-3-hydroxycyclobutyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

To a mixture of4′-{[4-(trans-3-acetylcyclobutyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile(0.49 g), 30% hydrogen peroxide (8.3 mL) and chloroform (10 mL) wasgradually added dropwise trifluoroacetic acid anhydride (5.6 mL), andthe mixture was heated under reflux for 14 hr. Saturated aqueous sodiumhydrogen carbonate solution and aqueous sodium thiosulfate solution weregradually added to the reaction mixture, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated brine,and dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure, and the residue was mixed with tetrahydrofuran(5 mL), methanol (5 mL) and 1 M aqueous sodium hydroxide solution (5mL). The mixture was stirred at room temperature for 4 hr, and thereaction mixture was neutralized with 1 M hydrochloric acid. Afterevaporation of the solvent under reduced pressure, and the residue wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.29 g, 62%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.19 Hz, 3H) 1.48-1.71 (m, 2H)2.07-2.24 (m, 2H) 2.80-3.05 (m, 2H) 3.09-3.29 (m, 2H) 3.97 (s, 2H)4.33-4.61 (m, 1H) 5.11 (d, J=4.92 Hz, 1H) 5.51-5.88 (m, 1H) 7.21-7.50(m, 3H) 7.54-7.71 (m, 2H) 7.73-7.88 (m, 1H) 7.95 (d, J=7.95 Hz, 1H) 8.22(s, 1H)

Reference Example 384 ethyl[(trans-3-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclobutyl)oxy]acetate

A mixture of3′-fluoro-4′-{[4-(trans-3-hydroxycyclobutyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.29 g), rhodium(II) acetate (dimer) (0.0028 g) and toluene (3 mL) washeated to 80° C. under an argon atmosphere, a solution of ethyldiazoacetate (0.16 g) in toluene (3 mL) was added dropwise, and themixture was stirred at 80° C. for 10 min. The reaction mixture wasconcentrated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.95 g, 27%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.35 Hz, 3H) 1.26-1.36 (m,3H) 1.61-1.82 (m, 2H) 2.39-2.68 (m, 2H) 2.95-3.12 (m, 2H) 3.18-3.43 (m,2H) 4.02 (s, 2H) 4.05 (s, 2H) 4.24 (q, J=7.10 Hz, 2H) 4.49-4.67 (m, 1H)5.77-6.02 (m, 1H) 7.21-7.31 (m, 2H) 7.33-7.57 (m, 3H) 7.58-7.71 (m, 1H)7.72-7.80 (m, 1H) 7.93 (s, 1H)

Reference Example 3853′-fluoro-4′-({4-[trans-3-(2-hydroxy-2-methylpropoxy)cyclobutyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

Ethyl[(trans-3-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclobutyl)oxy]acetate(0.13 g) was dissolved in tetrahydrofuran (2 mL), methylmagnesiumbromide (0.62 mL, 1.0 M tetrahydrofuran solution) was added dropwise at0° C., and the mixture was stirred at 0° C. for 1 hr. Methylmagnesiumbromide (0.62 mL, 1.0 M tetrahydrofuran solution) was added, and themixture was stirred at room temperature for 1 hr. The reaction mixturewas added to 1 M hydrochloric acid, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.059 g,45%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.38 Hz, 3H) 1.24 (s, 6H)1.58-1.83 (m, 2H) 2.30 (s, 1H) 2.37-2.57 (m, 2H) 2.94-3.11 (m, 2H) 3.22(s, 2H) 3.24-3.44 (m, 2H) 4.02 (s, 2H) 4.31-4.57 (m, 1H) 5.69-6.03 (m,1H) 7.15-7.30 (m, 2H) 7.30-7.52 (m, 3H) 7.58-7.71 (m, 1H) 7.75 (d,J=7.95 Hz, 1H) 7.94 (s, 1H)

Reference Example 386 ethyl[(trans-4-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}-1-methylcyclohexyl)oxy]acetate

3′-Fluoro-4′-{[2-methyl-5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(12 g) was dissolved in tetrahydrofuran (120 mL), methylmagnesiumbromide (49 mL, 1.0 M tetrahydrofuran solution) was added dropwise at70° C., and the mixture was stirred at 70° C. for 2 hr. The reactionmixture was added to 1 M hydrochloric acid, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue obtained bysilica gel column chromatography was mixed with rhodium(II) acetate(dimer) (0.0080 g) and toluene (10 mL). A solution of ethyl diazoacetate(0.48 g) in toluene (10 mL) was added dropwise at 80° C. under an argonatmosphere, and the mixture was stirred at 80° C. for 10 min. Thereaction mixture was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.26 g, 1.7%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.25 Hz, 3H) 1.17-1.22 (m, 3H)1.32 (s, 3H) 1.46-1.89 (m, 8H) 2.37 (s, 3H) 2.54-2.76 (m, 2H) 2.80-3.04(m, 2H) 3.95 (s, 2H) 4.05-4.17 (m, 4H) 4.72-4.99 (m, 1H) 7.04-7.39 (m,2H) 7.45 (dd, J=11.11, 1.32 Hz, 1H) 7.52-7.70 (m, 2H) 7.73-7.85 (m, 1H)7.95 (dd, J=7.63, 1.04 Hz, 1H)

Reference Example 3873′-fluoro-4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)-4-methylcyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

Ethyl[(trans-4-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}-1-methylcyclohexyl)oxy]acetate(0.26 g) was dissolved in tetrahydrofuran (3 mL), methylmagnesiumbromide (1.1 mL, 1.0 M tetrahydrofuran solution) was added dropwise at0° C., and the mixture was stirred at room temperature for 1 hr. Thereaction mixture was added to 1 M hydrochloric acid, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.19 g, 75%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.19 Hz, 3H) 1.06 (s, 6H) 1.30(s, 3H) 1.36-1.87 (m, 8H) 2.37 (s, 3H) 2.53-2.75 (m, 2H) 2.82-3.00 (m,2H) 3.12 (s, 2H) 3.95 (s, 2H) 4.13 (s, 1H) 4.67-5.02 (m, 1H) 7.19-7.39(m, 2H) 7.40-7.51 (m, 1H) 7.52-7.67 (m, 2H) 7.70-7.88 (m, 1H) 7.95 (d,J=6.44 Hz, 1H)

Reference Example 3881-[1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclobutyl]ethanol

Methylmagnesium bromide (21 mL, 1.0 M tetrahydrofuran solution) wascooled to 0° C., a solution of1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclobutanecarbaldehyde (4.0g) in tetrahydrofuran (40 mL) was added dropwise, and the mixture wasstirred at 0° C. for 1 hr. Methylmagnesium bromide (10 mL, 1.0 Mtetrahydrofuran solution) was added, and the mixture was stirred at 0°C. for 30 min. The reaction mixture was added to saturated aqueousammonium chloride solution, and the mixture was extracted with ethylacetate. The organic layer was dried over anhydrous magnesium sulfate,and the solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography to give the title compoundas an oily compound (2.5 g, 58%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.04 (s, 6H) 0.88 (s, 9H) 0.97 (d, J=6.44Hz, 3H) 1.52-2.09 (m, 6H) 3.46-3.69 (m, 3H) 4.30 (d, J=4.92 Hz, 1H)

Reference Example 389 1-[1-(hydroxymethyl)cyclobutyl]ethanol

1-[1-({[tert-Butyl(dimethyl)silyl]oxy}methyl)cyclobutyl]ethanol (3.2 g)was dissolved in tetrahydrofuran (30 mL), tetrabutylammonium fluoride(32 mL, 1.0 M tetrahydrofuran solution) was added dropwise, and themixture was stirred at room temperature for 5 hr. The reaction mixturewas added to 1 M hydrochloric acid, and the mixture was extracted withethyl acetate/2-propanol (3/1). The organic layer was dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography to give the title compound as an oily compound (1.3 g,79%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.97 (d, J=6.06 Hz, 3H) 1.49-1.95 (m, 6H)3.24-3.78 (m, 3H) 4.20-4.60 (m, 2H)

Reference Example 3903′-fluoro-4′-{[4-(5-methyl-6,13-dioxadispiro[3.2.5.2]tetradec-10-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of3′-fluoro-4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(23 g), 1-[1-(hydroxymethyl)cyclobutyl]ethanol (7.6 g),4-methylbenzenesulfonic acid (0.093 g) and toluene (200 mL) was heatedwith a Dean-Stark apparatus under reflux for 2 hr. The reaction mixturewas concentrated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (26 g, 90%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.19 Hz, 3H) 1.07-3.11 (m, 21H)3.59-3.89 (m, 3H) 3.97 (s, 2H) 4.72-5.04 (m, 1H) 7.23-7.40 (m, 2H) 7.45(d, J=10.98 Hz, 1H) 7.54-7.69 (m, 2H) 7.72-7.84 (m, 1H) 7.95 (d, J=7.57Hz, 1H) 8.17-8.23 (m, 1H)

Reference Example 3913′-fluoro-4′-[(4-{4-[1-(1-formylcyclobutyl)ethoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

A mixture of3′-fluoro-4′-{[4-(5-methyl-6,13-dioxadispiro[3.2.5.2]tetradec-10-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.64 g), sodium cyanoborohydride (0.33 g), boron trifluoride etherate(0.67 mL) and tetrahydrofuran (6 mL) was stirred at 70° C. for 20 hr.Saturated aqueous sodium hydrogen carbonate solution was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The residue obtained by purification by silica gel column chromatographywas mixed with Dess-Martin periodinane (0.49 g) and acetonitrile (5 mL),and the mixture was stirred at room temperature for 4 hr. Saturatedaqueous sodium hydrogen carbonate solution and aqueous sodiumthiosulfate solution were added to the reaction mixture, and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.21 g, 32%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=6.82 Hz, 3H) 1.01-1.11 (m, 3H)1.21-2.37 (m, 14H) 2.53-3.09 (m, 4H) 3.33-3.75 (m, 1H) 3.77-3.94 (m, 1H)3.97 (s, 2H) 4.73-5.07 (m, 1H) 7.20-7.38 (m, 2H) 7.45 (dd, J=10.98, 1.51Hz, 1H) 7.51-7.70 (m, 2H) 7.72-7.87 (m, 1H) 7.95 (d, J=7.57 Hz, 1H)8.09-8.27 (m, 1H) 9.54-9.85 (m, 1H)

Reference Example 3923′-fluoro-4′-{[4-(4-{1-[1-(1-hydroxyethyl)cyclobutyl]ethoxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

3′-Fluoro-4′-[(4-{4-[1-(1-formylcyclobutyl)ethoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(14 g) was dissolved in tetrahydrofuran (150 mL), methylmagnesiumbromide (35 mL, 1.0 M tetrahydrofuran solution) was added dropwise at 0°C., and the mixture was stirred at room temperature for 30 min. Thereaction mixture was added to 1 M hydrochloric acid, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (13 g, 90%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.88-1.17 (m, 9H) 1.21-2.22 (m, 14H)2.53-3.11 (m, 4H) 3.33-3.81 (m, 3H) 3.98 (s, 2H) 4.18-4.39 (m, 1H)4.73-5.05 (m, 1H) 7.23-7.51 (m, 3H) 7.53-7.69 (m, 2H) 7.72-7.86 (m, 1H)7.95 (d, J=7.95 Hz, 1H) 8.10-8.27 (m, 1H)

Reference Example 3934′-[(4-{4-[1-(1-acetylcyclobutyl)ethoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile

A mixture of3′-fluoro-4′-{[4-(4-{1-[1-(1-hydroxyethyl)cyclobutyl]ethoxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(13 g), Dess-Martin periodinane (10 g) and acetonitrile (130 mL) wasstirred at room temperature for 30 min. Saturated aqueous sodiumhydrogen carbonate solution and 1 M aqueous sodium thiosulfate solutionwere added to the reaction mixture, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (11 g,88%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.85-1.00 (m, 6H) 1.22-2.39 (m, 17H)2.54-3.07 (m, 4H) 3.34-3.73 (m, 1H) 3.74-3.92 (m, 1H) 3.98 (s, 2H)4.78-5.08 (m, 1H) 7.23-7.50 (m, 3H) 7.55-7.70 (m, 2H) 7.74-7.85 (m, 1H)7.95 (d, J=7.95 Hz, 1H) 8.08-8.28 (m, 1H)

Reference Example 3943′-fluoro-4′-[(4-{trans-4-[1-(1-hydroxycyclobutyl)ethoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

To a mixture of4′-[(4-{4-[1-(1-acetylcyclobutyl)ethoxy]cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl}-3′-fluorobiphenyl-2-carbonitrile(11 g), 30% hydrogen peroxide (157 mL) and chloroform (150 mL) wasgradually added dropwise trifluoroacetic acid anhydride (105 mL), andthe mixture was stirred at 60° C. for 24 hr and then at room temperaturefor 40 hr. Saturated aqueous sodium hydrogen carbonate solution andaqueous sodium thiosulfate solution were gradually added to the reactionmixture, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The residue was mixed with tetrahydrofuran (100 mL), methanol (100 mL)and 1 M aqueous sodium hydroxide solution (100 mL), and the mixture wasstirred at room temperature for 1 hr. The reaction mixture wasneutralized with 1 M hydrochloric acid. After evaporation of the solventunder reduced pressure, the residue was extracted with ethyl acetate.The organic layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (1.3 g,12%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.35 Hz, 3H) 1.01 (d, J=6.03 Hz,3H) 1.20-1.94 (m, 10H) 1.96-2.22 (m, 4H) 2.53-2.72 (m, 2H) 2.80-3.10 (m,2H) 3.26-3.49 (m, 2H) 3.97 (s, 2H) 4.65 (br. s., 1H) 4.78-4.99 (m, 1H)7.23-7.50 (m, 3H) 7.53-7.69 (m, 2H) 7.74-7.86 (m, 1H) 7.95 (d, J=7.91Hz, 1H) 8.20 (s, 1H)

Reference Example 3954′-{[4-(1-benzylpiperidin-4-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A solution of 1-benzyl-N-(1H-1,2,4-triazol-5-yl)-piperidine-4-amine(7.53 g) and ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate(14.41 g) in 1,2,4-trichlorobenzene (20 mL) was stirred at 195° C. for 2days. The reaction mixture was cooled to room temperature and purifiedby silica gel chromatography [eluent: hexane/ethyl acetate=65/35→50/50(volume ratio)] to give the title compound (4.82 g, 30%) as a brownamorphous compound.

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.4 Hz, 3H), 1.65-1.79 (m, 4H),2.13-2.20 (m, 2H), 2.89-3.05 (m, 6H), 3.55 (s, 2H), 4.01 (s, 2H),5.01-5.13 (m, 1H), 7.21-7.48 (m, 11H), 7.58-7.64 (m, 1H), 7.72-7.75 (m,1H), 7.92 (s, 1H).

Reference Example 3964′-[(5-oxo-4-piperidin-4-yl-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

A mixture of4′-{[4-(1-benzylpiperidin-4-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(4.82 g), 10% palladium-carbon (containing water by 50%, 2.39 g),tetrahydrofuran (30 mL) and ethanol (60 mL) was stirred at roomtemperature for 2 days under a hydrogen atmosphere. The reaction mixturewas filtered, and the solvent was evaporated. The residue was purifiedby basic silica gel chromatography [eluent: methanol/ethylacetate=0/100→5/95 (volume ratio)] to give the title compound as acolorless amorphous compound (2.97 g, 74%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.2 Hz, 3H), 1.67-1.79 (m, 4H),2.01 (br s, 1H), 2.70-2.81 (m, 4H), 3.01-3.06 (m, 2H), 3.23-3.26 (m,2H), 4.02 (s, 2H), 5.12-5.23 (m, 1H), 7.36 (d, J=8.1 Hz, 2H), 7.38-7.44(m, 1H), 7.46-7.50 (m, 3H), 7.59-7.64 (m, 1H), 7.72-7.75 (m, 1H), 7.91(s, 1H).

Reference Example 3974′-{[4-(1-ethylpiperidin-4-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-{[4-(1-benzylpiperidin-4-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(4.82 g), 10% palladium-carbon (2.39 g), tetrahydrofuran (30 mL) andethanol (60 mL) was stirred at room temperature for 2 days under ahydrogen atmosphere. The reaction mixture was filtered, and the solventwas evaporated. The residue was purified by basic silica gelchromatography [eluent: methanol/ethyl acetate=0/10→05/95 (volumeratio)] to give the title compound as a colorless amorphous compound(146 mg, 3%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.2 Hz, 3H), 1.13 (t, J=7.2 Hz,3H), 1.69-1.79 (m, 4H), 2.11-2.18 (m, 2H), 2.50 (q, J=7.2 Hz, 2H),2.92-3.15 (m, 6H), 4.01 (s, 2H), 5.05-5.15 (m, 1H), 7.36 (d, J=8.4 Hz,2H), 7.38-7.44 (m, 1H), 7.46-7.8 (m, 3H), 7.59-7.64 (m, 1H), 7.72-7.75(m, 1H), 7.90 (s, 1H).

Reference Example 3984′-({5-oxo-7-propyl-4-[1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl]-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-[(5-oxo-4-piperidin-4-yl-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(453 mg) and tetrahydropyran-4H-pyran-4-one (120 mg) in tetrahydrofuran(20 mL) was added sodium triacetoxyborohydride (318 mg), and the mixturewas stirred at room temperature for 15 hr. The reaction mixture wasdiluted with saturated aqueous sodium hydrogen carbonate solution, andthe mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue waspurified by basic silica gel chromatography [eluent: methanol/ethylacetate=0/10010/90 (volume ratio)] to give the title compound as acolorless amorphous compound (317 mg, 59%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.5 Hz, 3H), 1.55-1.79 (m, 8H),2.30-2.37 (m, 2H), 2.50-2.58 (m, 1H), 2.84-3.11 (m, 6H), 3.34-3.41 (m,2H), 4.01 (s, 2H), 4.01-4.05 (m, 2H), 5.00-5.11 (m, 1H), 7.36 (d, J=8.7Hz, 2H), 7.39-7.48 (m, 4H), 7.58-7.64 (m, 1H), 7.72-7.75 (m, 1H), 7.91(s, 1H).

Reference Example 3994′-({4-[4-(1-hydroxy-1-methylethyl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of ethyl4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexanecarboxylate(524 mg) in tetrahydrofuran (5 mL) was added 1 M methylmagnesiumbromide-tetrahydrofuran solution (5 mL), and the mixture was stirred atroom temperature for 15 hr. The reaction mixture was diluted withsaturated aqueous ammonium chloride solution, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel chromatography [eluent: hexane/ethyl acetate=70/30→50/50(volume ratio)] to give the title compound as a colorless amorphouscompound (388 mg, 76%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.5 Hz, 3H), 1.20 (s, 6H),1.23-1.35 (m, 1H), 1.43-1.55 (m, 1H), 1.69-1.86 (m, 6H), 1.99-2.04 (m,2H), 2.60-2.72 (m, 2H), 3.00-3.05 (m, 2H), 4.01 (s, 2H), 4.97-5.07 (m,1H), 7.29-7.51 (m, 4H), 7.59-7.64 (m, 1H), 7.74-7.76 (m, 1H), 7.91 (s,1H).

Reference Example 4004′-({5-oxo-7-propyl-4-[1-(tetrahydro-2H-pyran-4-ylcarbonyl)piperidin-4-yl]-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-[(5-oxo-4-piperidin-4-yl-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(453 mg), tetrahydropyran-2H-pyran-4-carboxylic acid (150 mg) and1-hydroxy-1H-benzotriazole (84 mg) in acetonitrile (20 mL) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (249 mg),and the mixture was stirred at room temperature for 15 hr. The reactionmixture was diluted with saturated aqueous sodium hydrogen carbonatesolution, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel chromatography [eluent: hexane/ethylacetate=35/65→0/100 (volume ratio)] to give the title compound as acolorless amorphous compound (518 mg, 92%).

¹H NMR (300 MHz, CDCl₃) δ 1.07 (t, J=7.5 Hz, 3H), 1.63-2.04 (m, 8H),2.61-2.95 (m, 4H), 3.01-3.06 (m, 2H), 3.14-3.23 (m, 1H), 3.42-3.50 (m,2H), 4.01 (s, 2H), 4.01-4.13 (m, 3H), 4.86 (br d, J=12.0 Hz, 1H),5.21-5.31 (m, 1H), 7.36 (d, J=8.7 Hz, 2H), 7.39-7.45 (m, 1H), 7.46-7.49(m, 3H), 7.60-7.65 (m, 1H), 7.73-7.76 (m, 1H), 7.89 (s, 1H).

Reference Example 4014′-({4-[1-(2-hydroxyethyl)piperidin-4-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-[(5-oxo-4-piperidin-4-yl-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(300 mg), 2-bromoethanol (170 mg), sodium carbonate (280 mg) and ethanol(20 mL) was stirred at 80° C. for 15 hr. Water was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by basic silica gel chromatography [eluent:hexane/ethyl acetate=35/65→0/100 (volume ratio)] to give the titlecompound as a colorless amorphous compound (205 mg, 63%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.2 Hz, 3H), 1.60-1.79 (m, 5H),2.17-2.31 (m, 2H), 2.58 (t, J=5.4 Hz, 2H), 2.87-3.08 (m, 6H), 3.61 (t,J=5.4 Hz, 2H), 4.01 (s, 2H), 5.04-5.14 (m, 1H), 7.36 (d, J=8.4 Hz, 2H),7.38-7.44 (m, 1H), 7.46-7.49 (m, 3H), 7.59-7.65 (m, 1H), 7.74 (d, J=8.1Hz, 1H), 7.92 (s, 1H).

Reference Example 4024′-({5-oxo-4-[trans-4-(2-oxoethoxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(different production method of the same compound as Reference Example325)

To a solution of4′-({4-[trans-4-(2-hydroxyethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(1.19 g) in acetonitrile (20 mL) was added1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (1.27 g) underice-cooling, and the mixture was stirred at room temperature for 3 days.The reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel chromatography [eluent:hexane/ethyl acetate=65/35→40/60 (volume ratio)] to give the titlecompound as a colorless amorphous compound (739 mg, 63%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.2 Hz, 3H), 1.46-1.59 (m, 2H),1.66-1.84 (m, 4H), 2.21 (br d, J=11.7 Hz, 2H), 2.64-2.78 (m, 2H),3.00-3.05 (m, 2H), 3.46-3.55 (m, 1H), 4.01 (s, 2H), 4.13 (s, 2H),5.03-5.13 (m, 1H), 7.35 (d, J=8.4 Hz, 2H), 7.39-7.44 (m, 1H), 7.46-7.49(m, 3H), 7.59-7.65 (m, 1H), 7.72-7.75 (m, 1H), 7.90 (s, 1H), 9.73 (s,1H).

Reference Example 4034′-({4-[trans-4-(2-hydroxypropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-({5-oxo-4-[trans-4-(2-oxoethoxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(841 mg) in tetrahydrofuran (15 mL) was added 1 M methylmagnesiumbromide-tetrahydrofuran solution (2.2 mL), and the mixture was stirredat room temperature for 15 hr. The reaction mixture was diluted withsaturated aqueous ammonium chloride solution, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified by basicsilica gel chromatography [eluent: hexane/ethyl acetate=70/30→40/60(volume ratio)] to give the title compound as a colorless amorphouscompound (387 mg, 76%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.5 Hz, 3H), 1.15 (d, J=6.3 Hz,3H), 1.40-1.52 (m, 2H), 1.66-1.83 (m, 4H), 2.17-2.21 (m, 2H), 2.56 (brs, 1H), 2.64-2.78 (m, 2H), 3.00-3.06 (m, 2H), 3.26 (dd, J=9.3, 8.1 Hz,1H), 3.40-3.52 (m, 2H), 3.91-3.96 (m, 1H), 4.02 (s, 2H), 5.03-5.11 (m,1H), 7.36 (d, J=8.7 Hz, 2H), 7.39-7.49 (m, 4H), 7.59-7.65 (m, 1H),7.72-7.75 (m, 1H), 7.91 (s, 1H).

Reference Example 404 methyl(4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}piperidin-1-yl)acetate

A mixture of4′-[(5-oxo-4-piperidin-4-yl-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(453 mg), ethyl bromoacetate (184 mg), potassium carbonate (276 mg) andN,N-dimethylformamide (5 mL) was stirred at 60° C. for 16 hr. Water wasadded to the reaction mixture, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel chromatography[eluent: hexane/ethyl acetate=60/40→35/65 (volume ratio)] to give thetitle compound as a colorless amorphous compound (418 mg, 80%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.5 Hz, 3H), 1.66-1.79 (m, 4H),2.44-2.52 (m, 2H), 2.96-3.08 (m, 6H), 3.32 (s, 2H), 3.72 (s, 3H), 4.02(s, 2H), 5.05-5.13 (m, 1H), 7.37 (d, J=8.4 Hz, 2H), 7.39-7.44 (m, 1H),7.46-7.49 (m, 3H), 7.59-7.65 (m, 1H), 7.72-7.75 (m, 1H), 7.90 (s, 1H).

Reference Example 4054′-({4-[1-(2-hydroxy-2-methylpropyl)piperidin-4-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of methyl(4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}piperidin-1-yl)acetate(418 mg) in tetrahydrofuran (6 mL) was added 1 M methylmagnesiumbromide-tetrahydrofuran solution (3 mL), and the mixture was stirred atroom temperature for 15 hr. The reaction mixture was diluted withsaturated aqueous ammonium chloride solution, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel chromatography [eluent: hexane/ethyl acetate=40/60→0/100(volume ratio)] to give the title compound as a colorless amorphouscompound (325 mg, 77%).

¹H NMR (300 MHz, CDCl₃) δ 1.07 (t, J=7.2 Hz, 3H), 1.18 (s, 6H),1.64-1.77 (m, 5H), 2.37 (s, 2H), 2.55 (br t, J=12.0 Hz, 2H), 2.89-3.06(m, 6H), 4.01 (s, 2H), 4.99-5.09 (m, 1H), 7.36 (d, J=8.4 Hz, 2H),7.38-7.44 (m, 1H), 7.46-7.49 (m, 3H), 7.59-7.64 (m, 1H), 7.72-7.75 (m,1H), 7.93 (s, 1H).

Reference Example 406

4′-({5-oxo-4-[trans-4-(2-oxopropoxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(different production method of the same compound as Reference Example212)

To a solution of4′-({4-[trans-4-(2-hydroxypropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(280 mg) in acetonitrile (5 mL) was added1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (293 mg) underice-cooling, and the mixture was stirred at room temperature for 16 hr.The reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel chromatography [eluent:hexane/ethyl acetate=65/35→40/60 (volume ratio)] to give the titlecompound as a colorless amorphous compound (254 mg, 92%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.5 Hz, 3H), 1.44-1.58 (m, 2H),1.65-1.85 (m, 4H), 2.18 (s, 3H), 2.18-2.23 (m, 2H), 2.63-2.77 (m, 2H),3.00-3.05 (m, 2H), 3.40-3.50 (m, 1H), 4.01 (s, 2H), 4.09 (s, 2H),5.02-5.12 (m, 1H), 7.35 (d, J=8.4 Hz, 2H), 7.39-7.44 (m, 1H), 7.46-7.49(m, 3H), 7.59-7.65 (m, 1H), 7.72-7.75 (m, 1H), 7.90 (s, 1H).

Reference Example 4074′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-({5-oxo-4-[trans-4-(2-oxopropoxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(251 mg) in tetrahydrofuran (3 mL) was added 1 M methylmagnesiumbromide-tetrahydrofuran solution (1 mL), and the mixture was stirred atroom temperature for 16 hr. The reaction mixture was diluted withsaturated aqueous ammonium chloride solution, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified by basicsilica gel chromatography [eluent: hexane/ethyl acetate=70/30→40/60(volume ratio)] to give the title compound as a colorless amorphouscompound (237 mg, 91%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.5 Hz, 3H), 1.20 (s, 6H),1.39-1.50 (m, 2H), 1.66-1.82 (m, 4H), 2.17-2.20 (m, 2H), 2.37 (br s,1H), 2.63-2.77 (m, 2H), 3.00-3.05 (m, 2H), 3.30 (s, 2H), 3.39-3.49 (m,1H), 4.01 (s, 2H), 5.01-5.12 (m, 1H), 7.35 (d, J=8.7 Hz, 2H), 7.39-7.44(m, 1H), 7.45-7.49 (m, 3H), 7.59-7.64 (m, 1H), 7.72-7.75 (m, 1H), 7.90(s, 1H).

Reference Example 4084′-[(4-{1-[4-(benzyloxy)phenyl]piperidin-4-yl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

A mixture of4′-[(5-oxo-4-piperidin-4-yl-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(452 mg), 4-benzyloxyphenylboric acid (456 mg), copper(II) acetate (276mg), molecular sieves 4A (1.50 g), triethylamine (506 mg), pyridine (396mg) and tetrahydrofuran (10 mL) was stirred at room temperature for 2days. Ethyl acetate was added to the reaction mixture, and the mixturewas filtered through Celite-basic silica gel. The solvent was evaporatedunder reduced pressure, and the residue was purified by silica gelchromatography [eluent: hexane/ethyl acetate=75/25→60/40 (volume ratio)]to give the title compound as a colorless amorphous compound (364 mg,57%).

¹H NMR (300 MHz, CDCl₃) δ 1.07 (t, J=7.5 Hz, 3H), 1.68-1.83 (m, 4H),2.77-2.85 (m, 2H), 3.02-3.16 (m, 4H), 4.03 (s, 2H), 5.01 (s, 2H),5.13-5.24 (m, 1H), 6.87-6.95 (m, 4H), 7.26-7.50 (m, 11H), 7.59-7.64 (m,1H), 7.71-7.74 (m, 1H), 7.92 (s, 1H).

Reference Example 4094′-({4-[1-(4-hydroxyphenyl)piperidin-4-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-[(4-{1-[4-(benzyloxy)phenyl]piperidin-4-yl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(364 mg), 10% palladium-carbon (containing water by 50%, 91 mg),tetrahydrofuran (10 mL) and methanol (10 mL) was stirred at roomtemperature for 16 hr under a hydrogen atmosphere. The reaction mixturewas filtered, and the solvent was evaporated. The residue was purifiedby preparative HPLC [eluent: 0.1% trifluoroacetic acid-containingacetonitrile/0.1% trifluoroacetic acid-containing water=5/95→100/0(volume ratio)] to give the title compound as a colorless amorphouscompound (183 mg, 59%).

¹H NMR (300 MHz, CDCl₃) δ 1.07 (t, J=7.5 Hz, 3H), 1.68-1.83 (m, 4H),2.72-2.80 (m, 2H), 3.02-3.15 (m, 4H), 3.59 (br d, J=11.7 Hz, 2H), 4.02(s, 2H), 4.70-5.10 (br, 1H), 5.11-5.21 (m, 1H), 6.76 (d, J=9.0 Hz, 2H),6.87 (d, J=9.0 Hz, 2H), 7.38 (d, J=8.7 Hz, 2H), 7.41-7.44 (m, 1H),7.46-7.50 (m, 3H), 7.59-7.65 (m, 1H), 7.72-7.75 (m, 1H), 7.93 (s, 1H).

Reference Example 4101-(1,4-dioxaspiro[4.5]dec-8-yloxy)-2-methylpropan-2-ol

To a solution of 1,4-dioxaspiro[4.5]decan-8-ol (4.90 g) inN,N-dimethylformamide (20 mL) was added 60% sodium hydride in oil (1.24g) under ice-cooling, and the mixture was stirred at room temperaturefor 1 hr. Isobutylene oxide (2.52 g) was added to this mixture, and themixture was stirred at 90° C. for 15 hr. The reaction mixture was cooledto room temperature and diluted with water, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel chromatography [eluent: hexane/ethyl acetate=90/10→70/30(volume ratio)] to give the title compound as a colorless oil (5.59 g,78%).

¹H NMR (300 MHz, CDCl₃) δ 1.20 (s, 6H), 1.52-1.61 (m, 2H), 1.68-1.83 (m,6H), 2.39 (m, 1H), 3.24 (s, 2H), 3.45 (br s, 1H), 3.94 (br s, 4H).

Reference Example 411 4-(2-hydroxy-2-methylpropoxy)cyclohexanone

A mixture of 1-(1,4-dioxaspiro[4.5]dec-8-yloxy)-2-methylpropan-2-ol(5.53 g), 3N hydrochloric acid (30 mL) and acetone (30 mL) was stirredat room temperature for 16 hr. The reaction mixture was diluted withwater, and the mixture was extracted with ethyl acetate. The extract waswashed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel chromatography [eluent: hexane/ethylacetate=80/20→60/40 (volume ratio)] to give the title compound as acolorless oil (3.25 g, 73%).

¹H NMR (300 MHz, CDCl₃) δ 1.24 (s, 6H), 1.90-2.00 (m, 2H), 2.08-2.18 (m,2H), 2.23-2.32 (m, 2H), 2.36 (br s, 1H), 2.52-2.63 (m, 2H), 3.34 (s,2H), 3.74-3.79 (m, 1H).

Reference Example 4124′-({4-[cis-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

1) To a solution of 3-amino-1H-1,2,4-triazole (1.46 g) and4-(2-hydroxy-2-methylpropoxy)cyclohexanone (3.25 g) in acetic acid (30mL) was added sodium triacetoxyborohydride (5.53 g), and the mixture wasstirred at room temperature for 15 hr. The solvent was evaporated underreduced pressure, and the residue was diluted with saturated aqueoussodium hydrogen carbonate solution, and the mixture was extracted withethyl acetate-isopropyl alcohol (3:1). The extract was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel chromatography [eluent: methanol/ethyl acetate=0/10→06/94(volume ratio)] to give colorless amorphous2-methyl-1-{[4-(1H-1,2,4-triazol-3-ylamino)cyclohexyl]oxy}propan-2-ol(2.84 g, 64%) as a diastereomixture.

2) A solution of2-methyl-1-{[4-(1H-1,2,4-triazol-3-ylamino)cyclohexyl]oxy}propan-2-ol(2.80 g) and ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate(7.69 g) in 1,2,4-trichlorobenzene (15 mL) was stirred at 195° C. for 2days. The reaction mixture was cooled to room temperature, and purifiedby silica gel chromatography [eluent: hexane/ethyl acetate=70/30→50/50(volume ratio)] to give the title compound as a brown amorphous compound(620 mg, 10%).

¹H NMR (300 MHz, CDCl₃) δ 1.05 (t, J=7.5 Hz, 3H), 1.30 (s, 6H),1.48-1.56 (m, 4H), 1.67-1.75 (m, 2H), 2.09-2.14 (m, 2H), 2.95-3.04 (m,4H), 3.28 (s, 2H), 3.66-3.69 (m, 2H), 4.01 (s, 2H), 5.12-5.23 (m, 1H),7.36 (d, J=8.1 Hz, 2H), 7.38-7.49 (m, 4H), 7.58-7.64 (m, 1H), 7.72-7.75(m, 1H), 7.91 (s, 1H).

Reference Example 4132-methyl-1-[(8-methyl-1,4-dioxaspiro[4.5]dec-8-yl)oxy]propan-2-ol

To a solution of 8-methyl-1,4-dioxaspiro[4.5]decan-8-ol (4.01 g) inN,N-dimethylformamide (20 mL) was added 60% sodium hydride in oil (960mg) under ice-cooling, and the mixture was stirred at room temperaturefor 1 hr. To this mixture was added isobutylene oxide (2.52 g), and themixture was stirred at 90° C. for 15 hr. The reaction mixture was cooledto room temperature, and diluted with water, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel chromatography [eluent: hexane/ethyl acetate=80/20→65/35(volume ratio)] to give the title compound as a colorless oil (1.81 g,32%).

¹H NMR (300 MHz, CDCl₃) δ 1.15 (s, 3H), 1.21 (s, 6H), 1.50-1.64 (m, 4H),1.76-1.82 (m, 4H), 2.43 (s, 1H), 3.12 (s, 2H), 3.45 (br s, 1H),3.92-3.95 (m, 4H).

Reference Example 4144-(2-hydroxy-2-methylpropoxy)-4-methylcyclohexanone

A mixture of2-methyl-1-[(8-methyl-1,4-dioxaspiro[4.5]dec-8-yl)oxy]propan-2-ol (1.81g), 3N hydrochloric acid (20 mL) and acetone (20 mL) was stirred at roomtemperature for 18 hr. The reaction mixture was diluted with water, andthe mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel chromatography [eluent: hexane/ethylacetate=80/20→65/35 (volume ratio)] to give the title compound as acolorless oil (1.05 g, 71%).

¹H NMR (300 MHz, CDCl₃) δ 1.26 (s, 9H), 1.70-1.81 (m, 2H), 2.11-2.25 (m,4H), 2.32 (br s, 1H), 2.54-2.65 (m, 2H), 3.25 (s, 2H).

Reference Example 4154′-({4-[cis-4-(2-hydroxy-2-methylpropoxy)-4-methylcyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

1) To a solution of 3-amino-1H-1,2,4-triazole (441 mg) and4-(2-hydroxy-2-methylpropoxy)-4-methylcyclohexanone (1.05 g) in aceticacid (10 mL) was added sodium triacetoxyborohydride (1.67 g), and themixture was stirred at room temperature for 15 hr. The solvent wasevaporated under reduced pressure, the residue was diluted withsaturated aqueous sodium hydrogen carbonate solution, and the mixturewas extracted with ethyl acetate-isopropyl alcohol (3:1). The extractwas washed with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel chromatography [eluent:methanol/ethyl acetate=0/100→10/90 (volume ratio)] to give colorlessamorphous2-methyl-1-{[1-methyl-4-(1H-1,2,4-triazol-3-ylamino)cyclohexyl]oxy}propan-2-ol(810 mg, 54%) as a diastereomixture.

2) A solution of2-methyl-1-{[1-methyl-4-(1H-1,2,4-triazol-3-ylamino)cyclohexyl]oxy}propan-2-ol(810 mg) and ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate(1.99 g) in 1,2,4-trichlorobenzene (10 mL) was stirred at 195° C. for 3days. The reaction mixture was cooled to room temperature, and purifiedby silica gel chromatography [eluent: hexane/ethyl acetate=70/30→50/50(volume ratio)] to give the title compound as a brown amorphous compound(223 mg, 14%).

¹H NMR (300 MHz, CDCl₃) δ 1.04 (t, J=7.2 Hz, 3H), 1.18 (s, 3H), 1.20 (s,6H), 1.36-1.50 (m, 4H), 1.64-1.77 (m, 2H), 1.97-2.01 (m, 2H), 2.93-3.08(m, 4H), 3.20 (s, 2H), 4.02 (s, 2H), 4.29 (br s, 1H), 5.11-5.22 (m, 1H),7.36 (d, J=8.1 Hz, 2H), 7.38-7.44 (m, 1H), 7.46-7.49 (m, 3H), 7.59-7.64(m, 1H), 7.72-7.75 (m, 1H), 7.94 (s, 1H).

Reference Example 4164′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)-4-methylcyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

1) To a solution of 3-amino-1H-1,2,4-triazole (441 mg) and4-(2-hydroxy-2-methylpropoxy)-4-methylcyclohexanone (1.05 g) in aceticacid (10 mL) was added sodium triacetoxyborohydride (1.67 g), and themixture was stirred at room temperature for 15 hr. The reaction mixturewas diluted with saturated aqueous sodium hydrogen carbonate solution,and the mixture was extracted with ethyl acetate-isopropyl alcohol(3:1). The extract was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel chromatography[eluent: methanol/ethyl acetate=0/100→10/90 (volume ratio)] to givecolorless amorphous2-methyl-1-{[1-methyl-4-(1H-1,2,4-triazol-3-ylamino)cyclohexyl]oxy}propan-2-ol(810 mg, 54%) as a diastereomixture.

2) A solution of2-methyl-1-{[1-methyl-4-(1H-1,2,4-triazol-3-ylamino)cyclohexyl]oxy}propan-2-ol(810 mg) and ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate(1.99 g) in 1,2,4-trichlorobenzene (10 mL) was stirred at 195° C. for 3days. The reaction mixture was cooled to room temperature, and purifiedby silica gel chromatography [eluent: hexane/ethyl acetate=70/30→50/50(volume ratio)] to give the title compound as a brown amorphous compound(104 mg, 7%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.2 Hz, 3H), 1.20 (s, 6H), 1.42 (s,3H), 1.61-1.78 (m, 6H), 1.84-1.89 (m, 2H), 2.49 (br s, 1H), 2.72-2.86(m, 2H), 2.99-3.04 (m, 2H), 3.24 (s, 2H), 4.02 (s, 2H), 5.01-5.12 (m,1H), 7.36 (d, J=8.1 Hz, 2H), 7.39-7.44 (m, 1H), 7.47-7.49 (m, 3H),7.59-7.65 (m, 1H), 7.72-7.75 (m, 1H), 7.91 (s, 1H).

Reference Example 4171-benzyl-N-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-5-amine

To a solution of 1-benzyl-1H-1,2,3-triazol-5-amine (835 mg) andtetrahydropyran-4H-pyran-4-one (481 mg) in acetic acid (10 mL) was addedsodium triacetoxyborohydride (1.53 g), and the mixture was stirred atroom temperature for 15 hr. The solvent was evaporated under reducedpressure, the residue was diluted with saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethylacetate-isopropyl alcohol (3:1). The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel chromatography [eluent: hexane/ethyl acetate=35/65→0/100(volume ratio)], and crystallized from diisopropyl ether to give thetitle compound as pale-beige crystals (573 mg, 46%).

¹H NMR (300 MHz, CDCl₃) δ 1.22-1.34 (m, 2H), 1.83-1.88 (m, 2H), 3.02 (brd, J=6.6 Hz, 1H), 3.11-3.23 (m, 1H), 3.35-3.43 (m, 2H), 3.79-3.86 (m,2H), 5.38 (s, 2H), 7.00 (s, 1H), 7.18-7.21 (m, 2H), 7.31-7.40 (m, 3H).

Reference Example 418N-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-5-amine

A mixture of1-benzyl-N-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-5-amine (450 mg),10% palladium-carbon (containing water by 50%, 450 mg), ammonium formate(631 mg), acetic acid (1.2 mL) and methanol (12 mL) was stirred at 60°C. for 16 hr under a nitrogen atmosphere. The reaction mixture wasfiltered, and the solvent was evaporated. The residue was diluted withsaturated aqueous sodium hydrogen carbonate solution, and the mixturewas extracted with ethyl acetate-isopropyl alcohol (3:1). The extractwas washed with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure to give thetitle compound as a white powder (209 mg, 73%).

¹H NMR (300 MHz, CDCl₃) δ 1.45-1.55 (m, 2H), 2.03-2.08 (m, 2H),3.46-3.55 (m, 3H), 3.63-3.65 (m, 1H), 3.97-4.04 (m, 2H), 7.06 (s, 1H),10.75-11.00 (br, 1H).

Reference Example 4194′-{[5-oxo-7-propyl-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro[1,2,3]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A solution of N-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-5-amine (260mg), ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (1.08 g) and1,8-diazabicyclo[5.4.0]undec-7-ene (236 mg) in N,N-diethylaniline (20mL) was stirred at 180° C. for 16 hr. The reaction mixture was dilutedwith ethyl acetate-tetrahydrofuran (1:1), and the mixture was washedwith 1 N hydrochloric acid and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel chromatography[eluent: hexane/ethyl acetate=50/50→10/90 (volume ratio)] to give thetitle compound as a brown amorphous compound (207 mg, 29%).

¹H NMR (300 MHz, CDCl₃) δ 1.09 (t, J=7.5 Hz, 3H), 1.69-1.74 (m, 2H),1.78-1.86 (m, 2H), 2.39-2.53 (m, 2H), 3.20-3.25 (m, 2H), 3.51-3.60 (m,2H), 4.05 (s, 2H), 4.10-4.17 (m, 2H), 5.24-5.35 (m, 1H), 7.38 (d, J=8.4Hz, 2H), 7.39-7.45 (m, 1H), 7.46-7.50 (m, 3H), 7.49 (d, J=8.4 Hz, 2H),7.60-7.65 (m, 1H), 7.63 (s, 1H), 7.73-7.76 (m, 1H).

Reference Example 4204′-({4-[(1R,3S,5S,7S)-5-hydroxytricyclo[3.3.1.1^(3,7)]dec-2-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(less polar isomer)

1) To a solution of 3-amino-1H-1,2,4-triazole (841 mg) and5-hydroxy-2-adamantanone (1.66 g) in acetic acid (10 mL) was addedsodium triacetoxyborohydride (3.18 g), and the mixture was stirred atroom temperature for 15 hr. The solvent was evaporated under reducedpressure, and the residue was diluted with saturated aqueous sodiumhydrogen carbonate solution, and the mixture was extracted with ethylacetate-isopropyl alcohol (3:1). The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was crystallized fromethyl acetate to give colorless solid(1S,3R,5S,7S)-4-(1H-1,2,4-triazol-3-ylamino)tricyclo[3.3.1.1^(3,7)]decan-1-ol(1.50 g, 64%) as a diastereomixture.

2)(1S,3R,5S,7S)-4-(1H-1,2,4-Triazol-3-ylamino)tricyclo[3.3.1.1^(3,7)]decan-1-ol(1.01 g), and a solution of ethyl2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (3.01 g) and1,8-diazabicyclo[5.4.0]undec-7-ene (655 mg) in N,N-diethylaniline (5 mL)were stirred at 180° C. for 16 hr. The reaction mixture was diluted with10% methanol-containing ethyl acetate, and the mixture was washed with 1N hydrochloric acid and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel chromatography[eluent: hexane/ethyl acetate=50/50→10/90 (volume ratio)] to give thetitle compound as a brown amorphous compound (90 mg, 4%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.5 Hz, 3H), 1.66-1.82 (m, 7H),1.91-1.95 (m, 2H), 2.23 (br s, 1H), 2.32 (br d, J=12.0 Hz, 2H),3.00-3.05 (m, 4H), 4.00 (s, 2H), 4.73-4.90 (m, 3H), 5.11-5.22 (m, 1H),7.34 (d, J=8.4 Hz, 2H), 7.38-7.44 (m, 1H), 7.45-7.49 (m, 3H), 7.59-7.64(m, 1H), 7.72-7.74 (m, 1H), 7.91 (s, 1H).

Reference Example 4214′-({4-[(1R,3S,5S,7S)-5-hydroxytricyclo[3.3.1.1^(3,7)]dec-2-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(highly-polar isomer)

1) To a solution of 3-amino-1H-1,2,4-triazole (841 mg) and5-hydroxy-2-adamantanone (1.66 g) in acetic acid (10 mL) was addedsodium triacetoxyborohydride (3.18 g), and the mixture was stirred atroom temperature for 15 hr. The solvent was evaporated under reducedpressure. The residue was diluted with saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethylacetate-isopropyl alcohol (3:1). The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was crystallized fromethyl acetate to give colorless solid(1S,3R,5S,7S)-4-(1H-1,2,4-triazol-3-ylamino)tricyclo[3.3.1.1^(3,7)]decan-1-ol(1.50 g, 64%) as a diastereomixture.

2)(1S,3R,5S,7S)-4-(1H-1,2,4-Triazol-3-ylamino)tricyclo[3.3.1.1^(3,7)]decan-1-ol(1.01 g), and a solution of ethyl2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (3.01 g) and1,8-diazabicyclo[5.4.0]undec-7-ene (655 mg) in N,N-diethylaniline (5 mL)were stirred at 180° C. for 16 hr. The reaction mixture was diluted with10% methanol-containing ethyl acetate, and the mixture was washed with 1N hydrochloric acid and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel chromatography[eluent: hexane/ethyl acetate=50/50→10/90 (volume ratio)] to give thetitle compound as a brown amorphous compound (99 mg, 4%).

¹H NMR (300 MHz, CDCl₃) δ 1.05 (t, J=7.5 Hz, 3H), 1.53-1.89 (m, 9H),2.01-2.04 (m, 2H), 2.19-2.27 (m, 3H), 2.98-3.04 (m, 4H), 4.01 (s, 2H),4.82 (br s, 1H), 7.34 (d, J=8.4 Hz, 2H), 7.38-7.44 (m, 1H), 7.45-7.48(m, 3H), 7.59-7.64 (m, 1H), 7.72-7.75 (m, 1H), 7.89 (s, 1H).

Reference Example 4224′-({4-[cis-4-(but-3-en-1-yl)-4-hydroxycyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of ice-cooled cerium(III) chloride in tetrahydrofuran (10mL) was added dropwise 0.5M 3-butenylmagnesium bromide-tetrahydrofuransolution (9.6 mL) under an argon atmosphere, and the mixture was stirredat 0° C. for 30 min. A solution of4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(1.86 g) in tetrahydrofuran (10 mL) was added dropwise to this reactionmixture, and the mixture was stirred at 0° C. for 30 min and then atroom temperature for 15 hr. The reaction mixture was diluted withsaturated aqueous ammonium chloride solution, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified by basicsilica gel chromatography [eluent: hexane/ethyl acetate=80/20→50/50(volume ratio)] to give the title compound as a colorless amorphouscompound (506 mg, 24%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.2 Hz, 3H), 1.49-1.85 (m, 11H),2.16-2.26 (m, 2H), 2.89-3.06 (m, 4H), 4.02 (s, 2H), 4.94-5.13 (m, 3H),5.80-5.93 (m, 1H), 7.37 (d, J=8.1 Hz, 2H), 7.38-7.44 (m, 1H), 7.46-7.49(m, 3H), 7.59-7.65 (m, 1H), 7.72-7.75 (m, 1H), 7.93 (s, 1H).

Reference Example 4234′-({4-[trans-4-(but-3-en-1-yl)-4-hydroxycyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of ice-cooled cerium(III) chloride in tetrahydrofuran (10mL) was added dropwise 0.5M 3-butenylmagnesium bromide-tetrahydrofuransolution (9.6 mL) under an argon atmosphere, and the mixture was stirredat 0° C. for 30 min. A solution of4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(1.86 g) in tetrahydrofuran (10 mL) was added dropwise to this reactionmixture, and the mixture was stirred at 0° C. for 30 min and then atroom temperature for 15 hr. The reaction mixture was diluted withsaturated aqueous ammonium chloride solution, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified by basicsilica gel chromatography [eluent: hexane/ethyl acetate=80/20→50/50(volume ratio)] to give the title compound as a colorless amorphouscompound (210 mg, 10%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.5 Hz, 3H), 1.41 (br s, 1H),1.58-1.78 (m, 6H), 1.90-1.96 (m, 4H), 2.18-2.26 (m, 2H), 2.69-2.84 (m,2H), 2.99-3.04 (m, 2H), 4.01 (s, 2H), 5.00-5.15 (m, 3H), 5.89-6.02 (m,1H), 7.36 (d, J=8.1 Hz, 2H), 7.39-7.44 (m, 1H), 7.46-7.49 (m, 3H),7.59-7.65 (m, 1H), 7.72-7.75 (m, 1H), 7.91 (s, 1H).

Reference Example 4244′-({4-[(5S,8S)-2-(hydroxymethyl)-1-oxaspiro[4.5]dec-8-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-({4-[cis-4-(but-3-en-1-yl)-4-hydroxycyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(506 mg) in acetonitrile (10 mL) was added m-chloroperbenzoic acid (365mg), and the mixture was stirred at room temperature for 2 days. Thereaction mixture was diluted with ethyl acetate, and the mixture waswashed with 5% aqueous sodium thiosulfate solution and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel chromatography [eluent: hexane/ethyl acetate=50/50→20/80(volume ratio)] to give the title compound as a colorless amorphouscompound (456 mg, 87%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.5 Hz, 3H), 1.49-2.01 (m, 11H),2.20-2.60 (br, 2H), 2.90-3.05 (m, 4H), 3.50 (dd, J=11.4, 6.0 Hz, 1H),3.74 (dd, J=11.4, 3.3 Hz, 1H), 4.02 (s, 2H), 4.10-4.20 (m, 1H),5.01-5.12 (m, 1H), 7.37 (d, J=8.7 Hz, 2H), 7.38-7.44 (m, 1H), 7.46-7.49(m, 3H), 7.59-7.65 (m, 1H), 7.72-7.75 (m, 1H), 7.93 (s, 1H).

Reference Example 4254′-({4-[(5R,8R)-2-(hydroxymethyl)-1-oxaspiro[4.5]dec-8-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-({4-[trans-4-(but-3-en-1-yl)-4-hydroxycyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(210 mg) in acetonitrile (10 mL) was added m-chloroperbenzoic acid (150mg), and the mixture was stirred at room temperature for 18 hr. Thereaction mixture was diluted with ethyl acetate, and the mixture waswashed with 5% aqueous sodium thiosulfate solution and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel chromatography [eluent: hexane/ethyl acetate=60/40→20/80(volume ratio)] to give the title compound as a colorless amorphouscompound (138 mg, 64%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.5 Hz, 3H), 1.66-1.91 (m, 9H),1.95-2.11 (m, 4H), 2.67-2.82 (m, 2H), 2.99-3.05 (m, 2H), 3.49 (dd,J=11.4, 5.4 Hz, 1H), 3.70 (dd, J=11.4, 3.3 Hz, 1H), 4.01 (s, 2H),4.08-4.17 (m, 1H), 5.03-5.14 (m, 1H), 7.36 (d, J=8.1 Hz, 2H), 7.39-7.44(m, 1H), 7.46-7.49 (m, 3H), 7.59-7.65 (m, 1H), 7.72-7.75 (m, 1H), 7.91(s, 1H).

Reference Example 4264′-({4-[(5S,8S)-2-(2-hydroxypropan-2-yl)-1-oxaspiro[4.5]dec-8-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-({4-[(5S,8S)-2-(hydroxymethyl)-1-oxaspiro[4.5]dec-8-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(456 mg) in acetonitrile (10 mL) was added1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (467 mg) underice-cooling, and the mixture was stirred at room temperature for 5 hr.The reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure. 1M Methylmagnesium bromide-tetrahydrofuran solution (1.3 mL) was added toa solution of the obtained residue in tetrahydrofuran (5 mL), and themixture was stirred at room temperature for 15 hr. The reaction mixturewas diluted with saturated aqueous ammonium chloride solution, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure.1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (331 mg) wasadded to a solution of the obtained residue in acetonitrile (10 mL)under ice-cooling, and the mixture was stirred at room temperature for 5hr. The reaction mixture was diluted with saturated aqueous sodiumhydrogen carbonate solution, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. 1 M Methylmagnesium bromide-tetrahydrofuran solution (0.9 mL)was added to a solution of the residue in tetrahydrofuran (5 mL), andthe mixture was stirred at room temperature for 15 hr. The reactionmixture was diluted with saturated aqueous ammonium chloride solution,and the mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel chromatography [eluent: hexane/ethylacetate=70/30→50/50 (volume ratio)] to give the title compound as abrown amorphous compound (158 mg, 33%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.5 Hz, 3H), 1.16 (s, 6H),1.51-1.89 (m, 12H), 2.10-2.60 (br, 1H), 2.95-3.08 (m, 4H), 3.81-3.86 (m,1H), 4.02 (s, 2H), 5.01-5.12 (m, 1H), 7.37 (d, J=8.1 Hz, 2H), 7.38-7.44(m, 1H), 7.47-7.50 (m, 3H), 7.59-7.65 (m, 1H), 7.72-7.75 (m, 1H), 7.90(s, 1H).

Reference Example 4271-benzyl-N-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-1,2,3-triazol-5-amine

To a solution of 1-benzyl-1H-1,2,3-triazol-5-amine (10.61 g) and4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexanone (15.07 g) in acetic acid(80 mL) was added sodium triacetoxyborohydride (19.37 g), and themixture was stirred at room temperature for 18 hr. The solvent wasevaporated under reduced pressure, the residue was diluted withsaturated aqueous sodium hydrogen carbonate solution, and the mixturewas extracted with ethyl acetate-isopropyl alcohol (3:1). The extractwas washed with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel chromatography [eluent: hexane/ethylacetate=80/20→60/40 (volume ratio)] to give the title compound as apale-yellow oil (11.12 g, 47%).

¹H NMR (300 MHz, CDCl₃) δ 0.02 (s, 6H), 0.87 (s, 9H), 1.30-1.95 (m, 8H),2.90-3.10 (m, 2H), 3.50-3.80 (m, 1H), 5.37 (s, 2H), 6.96 (s, 1H),7.16-7.22 (m, 2H), 7.31-7.39 (m, 3H).

Reference Example 428N-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-1,2,3-triazol-5-amine

A mixture of1-benzyl-N-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-1,2,3-triazol-5-amine(11.10 g), 10% palladium-carbon (containing water by 50%, 6.66 g),ammonium formate (9.05 g), acetic acid (22 mL) and methanol (220 mL) wasstirred at 60° C. for 16 hr under a nitrogen atmosphere. The reactionmixture was filtered, and the solvent was evaporated. The residue wasdiluted with saturated aqueous sodium hydrogen carbonate solution, andthe mixture was extracted with ethyl acetate-isopropyl alcohol (3:1).The extract was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by basic silica gel chromatography [eluent:hexane/ethyl acetate=70/30→30/70 (volume ratio)] to give the titlecompound as a colorless oil (5.56 g, 65%).

¹H NMR (300 MHz, CDCl₃) δ 0.06 (s, 6H), 0.91 (s, 9H), 1.20-2.13 (m, 8H),3.15-4.20 (m, 3H), 7.03 (s, 1H), 10.00-11.50 (br, 1H).

Reference Example 4294′-{[4-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,3]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

N-(4-{[tert-Butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-1,2,3-triazol-5-amine(5.55 g) and a solution of ethyl2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (13.07 g) and1,8-diazabicyclo[5.4.0]undec-7-ene (2.85 g) in N,N-diethylaniline (30mL) were stirred at 185° C. for 15 hr. The reaction mixture was dilutedwith ethyl acetate, and the mixture was washed with 1 N hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel chromatography [eluent: hexane/ethylacetate=90/10→80/20 (volume ratio)] to give the title compound as abrown amorphous compound (1.58 g, 15%).

¹H NMR (300 MHz, CDCl₃) δ 0.12 (s, 6H), 0.98 (s, 9H), 1.09 (t, J=7.5 Hz,3H), 1.51-2.05 (m, 8H), 2.20-2.60 (m, 2H), 3.17-3.24 (m, 2H), 3.60-4.07(m, 3H), 4.60-5.25 (m, 1H), 7.36-7.50 (m, 6H), 7.59-7.65 (m, 1H), 7.66(s, 1H), 7.72-7.75 (m, 1H).

Reference Example 4304′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,3]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-{[4-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,3]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(1.58 g) in tetrahydrofuran (10 mL) was added 1 M tetra-n-butylammoniumfluoride-tetrahydrofuran solution (10 mL), and the mixture was stirredat room temperature for 15 hr. Saturated aqueous ammonium chloridesolution was added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel chromatography [eluent: hexane/ethyl acetate=50/50→25/75(volume ratio)] to give the title compound as a colorless amorphouscompound (293 mg, 23%).

¹H NMR (300 MHz, CDCl₃) δ 1.09 (t, J=7.5 Hz, 3H), 1.48-1.62 (m, 3H),1.75-1.87 (m, 4H), 2.13-2.17 (m, 2H), 2.22-2.36 (m, 2H), 3.18-3.23 (m,2H), 3.71-3.81 (m, 1H), 4.03 (s, 2H), 4.75-4.95 (br, 1H), 7.37 (d, J=8.7Hz, 2H), 7.39-7.45 (m, 1H), 7.46-7.49 (m, 1H), 7.48 (d, J=8.7 Hz, 2H),7.49 (s, 1H), 7.59-7.65 (m, 1H), 7.73-7.76 (m, 1H).

Reference Example 431 ethyl[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,3]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate

To a mixture of4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,3]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(470 mg), rhodium(II) acetate (dimer) (22 mg) and methylene chloride (10mL) was added dropwise ethyl diazoacetate (137 mg) under an argonatmosphere, and the mixture was stirred at room temperature for 3 days.The reaction mixture was washed with water and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel chromatography [eluent: hexane/ethyl acetate=70/30→20/80(volume ratio)] to give the title compound as a colorless amorphouscompound (203 mg, 37%).

¹H NMR (300 MHz, CDCl₃) δ 1.09 (t, J=7.2 Hz, 3H), 1.30 (t, J=7.2 Hz,3H), 1.52-1.63 (m, 2H), 1.74-1.88 (m, 4H), 2.20-2.32 (m, 4H), 3.18-3.23(m, 2H), 3.41-3.51 (m, 1H), 4.03 (s, 2H), 4.14 (s, 2H), 4.23 (q, J=7.2Hz, 2H), 4.75-4.95 (br, 1H), 7.36 (d, J=8.7 Hz, 2H), 7.39-7.45 (m, 1H),7.46-7.49 (m, 1H), 7.48 (d, J=8.7 Hz, 2H), 7.48 (s, 1H), 7.60-7.65 (m,1H), 7.73-7.76 (m, 1H).

Reference Example 4324′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,3]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of ethyl[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,3]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate(203 mg) in tetrahydrofuran (5 mL) was added 1 M methylmagnesiumbromide-tetrahydrofuran solution (1.8 mL), and the mixture was stirredat room temperature for 15 hr. The reaction mixture was diluted withsaturated aqueous ammonium chloride solution, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel chromatography [eluent: hexane/ethyl acetate=50/50→30/70(volume ratio)] to give the title compound as a colorless amorphouscompound (153 mg, 77%).

¹H NMR (300 MHz, CDCl₃) δ 1.08 (t, J=7.2 Hz, 3H), 1.21 (s, 6H),1.42-1.55 (m, 2H), 1.74-1.88 (m, 4H), 2.17-2.27 (m, 4H), 2.32 (br s,1H), 3.18-3.23 (m, 2H), 3.32 (s, 2H), 3.34-3.42 (m, 1H), 4.03 (s, 2H),4.75-4.95 (br, 1H), 7.37 (d, J=8.4 Hz, 2H), 7.39-7.45 (m, 1H), 7.46-7.49(m, 1H), 7.49 (d, J=8.4 Hz, 2H), 7.49 (s, 1H), 7.60-7.65 (m, 1H),7.73-7.76 (m, 1H).

Reference Example 4334′-(4-[cis-4-hydroxy-4-(prop-2-en-1-yl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of tetraallyltin(IV) (142 mg), gadorinium chloride hexahydrate(19 mg),4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(466 mg), tetrahydrofuran (3 mL) and acetonitrile (5 mL) was stirred atroom temperature for 15 hr under an argon atmosphere. The reactionmixture was diluted with water, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by basic silica gelchromatography [eluent: hexane/ethyl acetate=70/30→40/60 (volume ratio)]to give the title compound as a colorless amorphous compound (383 mg,75%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.5 Hz, 3H), 1.51-1.99 (m, 9H),2.26 (d, J=7.5 Hz, 2H), 2.90-3.05 (m, 4H), 4.02 (s, 2H), 5.01-5.18 (m,3H), 5.84-5.98 (m, 1H), 7.37 (d, J=8.1 Hz, 2H), 7.38-7.44 (m, 1H),7.46-7.49 (m, 3H), 7.59-7.65 (m, 1H), 7.72-7.75 (m, 1H), 7.93 (s, 1H).

Reference Example 4344′-({4-[trans-4-hydroxy-(4-prop-2-en-1-yl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

A mixture of tetraallyltin(IV) (142 mg), gadorinium chloride hexahydrate(19 mg),4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(466 mg), tetrahydrofuran (3 mL) and acetonitrile (5 mL) was stirred atroom temperature for 15 hr under an argon atmosphere. The reactionmixture was diluted with water, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by basic silica gelchromatography [eluent: hexane/ethyl acetate=70/30→40/60 (volume ratio)]to give the title compound as a colorless amorphous compound (113 mg,22%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.5 Hz, 3H), 1.60-1.79 (m, 6H),1.86-1.91 (m, 2H), 2.62 (d, J=7.5 Hz, 2H), 2.74-2.89 (m, 2H), 2.99-3.05(m, 2H), 4.02 (s, 2H), 5.06-5.17 (m, 1H), 5.21-5.28 (m, 2H), 5.87-6.01(m, 1H), 7.36 (d, J=8.4 Hz, 2H), 7.39-7.44 (m, 1H), 7.46-7.50 (m, 3H),7.59-7.65 (m, 1H), 7.72-7.75 (m, 1H), 7.91 (s, 1H).

Reference Example 4354′-({4-[cis-4-hydroxy-4-(oxiran-2-ylmethyl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a mixture of4′-({4-[cis-4-hydroxy-4-(prop-2-en-1-yl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(548 mg), sodium hydrogen carbonate (136 mg) and methylene chloride (5mL) was added m-chloroperbenzoic acid (370 mg) at 0° C., and the mixturewas stirred at room temperature for 15 hr. The reaction mixture wasdiluted with ethyl acetate, and the mixture was washed with 5% aqueoussodium thiosulfate solution and then with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gelchromatography [eluent: hexane/ethyl acetate=60/40→35/65 (volume ratio)]to give the title compound as a colorless amorphous compound (490 mg,94%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.2 Hz, 3H), 1.55-1.79 (m, 7H),1.82-2.03 (m, 4H), 2.49 (dd, J=4.8, 2.7 Hz, 1H), 2.80 (dd, J=4.8, 4.2Hz, 1H), 2.92-3.05 (m, 4H), 3.16-3.22 (m, 1H), 4.02 (s, 2H), 5.05-5.16(m, 1H), 7.36 (d, J=8.4 Hz, 2H), 7.38-7.44 (m, 1H), 7.45-7.49 (m, 3H),7.59-7.64 (m, 1H), 7.72-7.75 (m, 1H), 7.93 (s, 1H).

Reference Example 4364′-({4-[trans-4-hydroxy-4-(oxiran-2-ylmethyl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a mixture of4′-({4-[trans-4-hydroxy-(4-prop-2-en-1-yl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(162 mg), sodium hydrogen carbonate (42 mg) and methylene chloride (3mL) was added m-chloroperbenzoic acid (118 mg) at 0° C., and the mixturewas stirred at room temperature for 15 hr. The reaction mixture wasdiluted with ethyl acetate, and the mixture was washed with 5% aqueoussodium thiosulfate solution and then with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gelchromatography [eluent: hexane/ethyl acetate=60/40→35/65 (volume ratio)]to give the title compound as a colorless amorphous compound (136 mg,81%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.5 Hz, 3H), 1.65-1.76 (m, 8H),1.95-1.99 (m, 1H), 2.08-2.12 (m, 1H), 2.44 (dd, J=14.7, 3.9 Hz, 1H),2.60 (dd, J=5.1, 2.7 Hz, 1H), 2.71-2.87 (m, 2H), 2.85 (dd, J=5.1, 3.9Hz, 1H), 2.99-3.04 (m, 2H), 3.21-3.27 (m, 1H), 4.01 (s, 2H), 5.07-5.18(m, 1H), 7.36 (d, J=8.7 Hz, 2H), 7.39-7.44 (m, 1H), 7.46-7.49 (m, 3H),7.59-7.65 (m, 1H), 7.72-7.75 (m, 1H), 7.90 (s, 1H).

Reference Example 4374′-({4-[(5S,8S)-3-hydroxy-1-oxaspiro[4.5]dec-8-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

Under an argon atmosphere, a mixture of a solution of4′-({4-[cis-4-hydroxy-4-(oxiran-2-ylmethyl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(245 mg) in tetrahydrofuran (5 mL) and magnesium bromide (18.4 mg) wasstirred at 60° C. for 20 hr. The reaction mixture was diluted withwater, and the mixture was extracted with ethyl acetate. The extract waswashed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue waspurified by basic silica gel chromatography [eluent: hexane/ethylacetate=50/50→20/80 (volume ratio)] to give the title compound as acolorless amorphous compound (238 mg, 97%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.2 Hz, 3H), 1.50-1.86 (m, 8H),1.96-2.18 (m, 3H), 2.99-3.05 (m, 4H), 3.88 (d, J=9.9 Hz, 1H), 3.97 (dd,J=9.9, 4.2 Hz, 1H), 4.02 (s, 2H), 4.46 (br s, 1H), 5.02-5.11 (m, 1H),7.35-7.48 (m, 6H), 7.59-7.64 (m, 1H), 7.72-7.74 (m, 1H), 7.94 (s, 1H).

Reference Example 4384′-({4-[(5R,8R)-3-hydroxy-1-oxaspiro[4.5]dec-8-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

Under an argon atmosphere, a mixture of a solution of4′-({4-[trans-4-hydroxy-4-(oxiran-2-ylmethyl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(136 mg) in tetrahydrofuran (3 mL) and magnesium bromide (9.6 mg) wasstirred at 60° C. for 20 hr. The reaction mixture was diluted with waterand the mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue waspurified by basic silica gel chromatography [eluent: hexane/ethylacetate=70/30→0/100 (volume ratio)] to give the title compound as acolorless amorphous compound (59 mg, 43%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.5 Hz, 3H), 1.66-1.89 (m, 8H),2.04-2.22 (m, 3H), 2.64-2.83 (m, 2H), 2.99-3.04 (m, 2H), 3.83 (dd,J=9.9, 2.4 Hz, 1H), 3.96 (dd, J=9.9, 4.5 Hz, 1H), 4.01 (s, 2H), 4.54 (brs, 1H), 5.04-5.12 (m, 1H), 7.35 (d, J=8.4 Hz, 2H), 7.38-7.44 (m, 1H),7.45-7.49 (m, 3H), 7.59-7.64 (m, 1H), 7.72-7.75 (m, 1H), 7.90 (s, 1H).

Reference Example 4394′-({5-oxo-4-[(5R,8R)-3-oxo-1-oxaspiro[4.5]dec-8-yl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-({4-[(5R,8R)-3-hydroxy-1-oxaspiro[4.5]dec-8-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(356 mg) in acetonitrile (10 mL) was added1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (433 mg) underice-cooling, and the mixture was stirred at room temperature for 16 hr.The reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel chromatography [eluent:hexane/ethyl acetate=50/50→30/70 (volume ratio)] to give the titlecompound as a colorless amorphous compound (345 mg, 97%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.2 Hz, 3H), 1.66-2.04 (m, 8H),2.67 (s, 2H), 2.67-2.80 (m, 2H), 3.00-3.06 (m, 2H), 4.01 (s, 2H), 4.06(s, 2H), 5.10-5.20 (m, 1H), 7.36 (d, J=8.1 Hz, 2H), 7.39-7.44 (m, 1H),7.47-7.50 (m, 3H), 7.59-7.65 (m, 1H), 7.72-7.75 (m, 1H), 7.90 (s, 1H).

Reference Example 4404′-({4-[(5R,8R)-3-hydroxy-3-methyl-1-oxaspiro[4.5]dec-8-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-({5-oxo-4-[(5R,8R)-3-oxo-1-oxaspiro[4.5]dec-8-yl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(181 mg) in tetrahydrofuran (3 mL) was added 2M methylmagnesiumiodide-diethyl ether solution (0.4 mL), and the mixture was stirred atroom temperature for 18 hr. The reaction mixture was diluted withsaturated aqueous ammonium chloride solution, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel chromatography [eluent: hexane/ethyl acetate=50/50→30/70(volume ratio)] to give the title compound as a colorless amorphouscompound (109 mg, 58%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.5 Hz, 3H), 1.43 (s, 3H),1.64-2.08 (m, 10H), 2.26 (d, J=13.8 Hz, 1H), 2.62-2.82 (m, 2H),2.99-3.04 (m, 2H), 3.68 (d, J=9.3 Hz, 1H), 3.79 (d, J=9.3 Hz, 1H), 4.01(s, 2H), 5.02-5.13 (m, 1H), 7.36 (d, J=8.4 Hz, 2H), 7.39-7.44 (m, 1H),7.45-7.49 (m, 3H), 7.59-7.65 (m, 1H), 7.72-7.75 (m, 1H), 7.91 (s, 1H).

Reference Example 4414′-({4-[(5R,8R)-3-ethyl-3-hydroxy-1-oxaspiro[4.5]dec-8-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-({5-oxo-4-[(5R,8R)-3-oxo-1-oxaspiro[4.5]dec-8-yl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(150 mg) in tetrahydrofuran (2 mL) was added 3M ethylmagnesiumbromide-diethyl ether solution (0.3 mL), and the mixture was stirred atroom temperature for 15 hr. The reaction mixture was diluted withsaturated aqueous ammonium chloride solution, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel chromatography [eluent: hexane/ethyl acetate=50/50→30/70(volume ratio)] to give the title compound as a colorless amorphouscompound (106 mg, 66%).

¹H NMR (300 MHz, CDCl₃) δ 1.03 (t, J=7.5 Hz, 3H), 1.06 (t, J=7.5 Hz,3H), 1.66-1.93 (m, 11H), 2.07-2.11 (m, 1H), 2.22 (d, J=13.5 Hz, 1H),2.62-2.81 (m, 2H), 2.99-3.04 (m, 2H), 3.71 (d, J=9.6 Hz, 1H), 3.78 (d,J=9.6 Hz, 1H), 4.01 (s, 2H), 5.03-5.11 (m, 1H), 7.36 (d, J=8.1 Hz, 2H),7.38-7.44 (m, 1H), 7.46-7.49 (m, 3H), 7.59-7.65 (m, 1H), 7.72-7.75 (m,1H), 7.91 (s, 1H).

Reference Example 442N-(1,4-dioxaspiro[4.5]dec-8-yl)-5-(trifluoromethyl)-1H-1,2,4-triazol-3-amine

To a solution of 5-(trifluoromethyl)-1H-1,2,4-triazol-3-amine (12.19 g)and 1,4-dioxaspiro[4.5]decan-8-one (12.49 g) in acetic acid (180 mL) wasadded sodium triacetoxyborohydride (25.43 g), and the mixture wasstirred at room temperature for 3 days. The solvent was evaporated underreduced pressure, the residue was diluted with saturated aqueous sodiumhydrogen carbonate solution, and the mixture was extracted with ethylacetate-isopropyl alcohol (3:1). The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel chromatography [eluent: methanol/ethyl acetate=0/100→10/90(volume ratio)] and crystallized from diisopropyl ether to give thetitle compound as a colorless solid (9.88 g, 42%).

¹H NMR (300 MHz, DMSO-d₆) δ 1.42-1.83 (m, 8H), 3.39 (br s, 1H),3.82-3.87 (m, 4H), 7.07 (d, J=8.1 Hz, 1H), 12.75 (br s, 1H).

Reference Example 4434′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-2-(trifluoromethyl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A solution ofN-(1,4-dioxaspiro[4.5]dec-8-yl)-5-(trifluoromethyl)-1H-1,2,4-triazol-3-amine(9.87 g), ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (23.59g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (5.05 mL) inN,N-diethylaniline (50 mL) was stirred at 180° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, and the mixture waswashed with 1 N hydrochloric acid and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gelchromatography [eluent: hexane/ethyl acetate=80/20→60/40 (volumeratio)], and crystallized from diisopropyl ether to give the titlecompound as a colorless solid (7.91 g, 41%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.2 Hz, 3H), 1.65-1.93 (m, 8H),2.87-3.08 (m, 4H), 3.93-4.03 (m, 6H), 5.00-5.08 (m, 1H), 7.35 (d, J=8.1Hz, 2H), 7.39-7.44 (m, 1H), 7.45-7.48 (m, 3H), 7.59-7.65 (m, 1H),7.72-7.75 (m, 1H).

Reference Example 4444′-{[4-(4-hydroxycyclohexyl)-5-oxo-7-propyl-2-(trifluoromethyl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-2-(trifluoromethyl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(7.69 g) in tetrahydrofuran (25 mL) was added 6N hydrochloric acid (25mL), and the mixture was stirred at 90° C. for 20 hr. The reactionmixture was cooled to room temperature, neutralized with 2 N aqueoussodium hydroxide solution, and extracted with ethyl acetate. The extractwas washed with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure. To asolution of the obtained residue in ethanol (20 mL)-tetrahydrofuran (10mL) was added sodium borohydride (631 mg) under ice-cooling, and themixture was stirred at room temperature for 8 hr. The reaction mixturewas concentrated under reduced pressure, and the residue was partitionedbetween ethyl acetate and water. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel chromatography [eluent: hexane/ethyl acetate=80/30→50/50(volume ratio)] to give the title compound as a colorless amorphouscompound (4.27 g, 60%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.2 Hz, 3H), 1.44-1.79 (m, 7H),2.11-2.15 (m, 2H), 2.64-2.78 (m, 2H), 3.00-3.06 (m, 2H), 3.77-3.88 (m,1H), 4.02 (s, 2H), 4.97-5.08 (m, 1H), 7.34 (d, J=8.4 Hz, 2H), 7.39-7.45(m, 1H), 7.46-7.49 (m, 3H), 7.60-7.65 (m, 1H), 7.73-7.76 (m, 1H).

Reference Example 445 ethyl[(4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl-2-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate

To a mixture of4′-{[4-(4-hydroxycyclohexyl)-5-oxo-7-propyl-2-(trifluoromethyl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(2.14 g), rhodium(II) acetate (dimer) (88 mg) and toluene (20 mL) wasadded dropwise ethyl diazoacetate (571 mg) under an argon atmosphere at80° C., and the mixture was stirred at 80° C. for 1 hr. The reactionmixture was concentrated under reduced pressure, and the residue waspurified by silica gel chromatography [eluent: hexane/ethylacetate=80/20→65/35 (volume ratio)] to give the title compound as acolorless amorphous compound (695 mg, 28%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.2 Hz, 3H), 1.30 (t, J=7.2 Hz,3H), 1.46-1.83 (m, 6H), 2.21-2.25 (m, 2H), 2.60-2.74 (m, 2H), 2.99-3.06(m, 2H), 3.46-3.56 (m, 1H), 4.02 (s, 2H), 4.14 (s, 2H), 4.22 (q, J=7.2Hz, 2H), 4.99-5.10 (m, 1H), 7.34 (d, J=8.4 Hz, 2H), 7.39-7.45 (m, 1H),7.46-7.49 (m, 3H), 7.59-7.65 (m, 1H), 7.72-7.76 (m, 1H).

Reference Example 4464′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-2-(trifluoromethyl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of ethyl[(4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl-2-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate(684 mg) in tetrahydrofuran (4 mL) was added 1 M methylmagnesiumbromide-tetrahydrofuran solution (4 mL), and the mixture was stirred atroom temperature for 15 hr. The reaction mixture was diluted withsaturated aqueous ammonium chloride solution, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel chromatography [eluent: hexane/ethyl acetate=80/20→40/60(volume ratio)] to give the title compound as a colorless amorphouscompound (472 mg, 70%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.2 Hz, 3H), 1.21 (s, 6H),1.65-1.81 (m, 4H), 2.17-2.21 (m, 2H), 2.34 (br s, 1H), 2.60-2.74 (m,2H), 3.00-3.06 (m, 2H), 3.32 (s, 2H), 3.40-3.50 (m, 1H), 4.02 (s, 2H),4.99-5.10 (m, 1H), 7.34 (d, J=8.7 Hz, 2H), 7.39-7.45 (m, 1H), 7.46-7.49(m, 3H), 7.60-7.65 (m, 1H), 7.73-7.76 (m, 1H).

Reference Example 4474′-({4-[cis-4-methoxy-4-(prop-2-en-1-yl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-({4-[cis-4-hydroxy-4-(prop-2-en-1-yl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(1.32 g) in tetrahydrofuran (10 mL) was added 60% sodium hydride in oil(120 mg) at 0° C., and the mixture was stirred at room temperature for30 min. Iodomethane (0.19 mL) was added and the mixture was furtherstirred for 15 hr. Water was added to the reaction mixture, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bybasic silica gel chromatography [eluent: hexane/ethylacetate=80/20→60/40 (volume ratio)] to give the title compound as acolorless amorphous compound (1.29 g, 97%).

¹H NMR (300 MHz, CDCl₃) δ 1.05 (t, J=7.2 Hz, 3H), 1.36-1.75 (m, 6H),1.98-2.02 (m, 2H), 2.24 (d, J=7.2 Hz, 2H), 2.85-3.04 (m, 4H), 3.28 (s,3H), 4.02 (s, 2H), 4.90-5.10 (m, 3H), 5.75-5.89 (m, 1H), 7.36 (d, J=8.4Hz, 2H), 7.38-7.49 (m, 4H), 7.59-7.64 (m, 1H), 7.72-7.75 (m, 1H), 7.91(s, 1H).

Reference Example 4484′-({4-[cis-4-(2-hydroxypropyl)-4-methoxycyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of dimethyl sulfide-borane (0.34 mL) in tetrahydrofuran (5mL) was added dropwise a solution of4′-({4-[cis-4-methoxy-4-(prop-2-en-1-yl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(1.66 g) in tetrahydrofuran (10 mL) at 0° C., and the mixture wasstirred at room temperature for 2 hr. The reaction mixture was cooled to0° C., 8N aqueous sodium hydroxide solution (2.5 mL) and then 30%aqueous hydrogen peroxide solution (3.5 mL) were added, and the mixturewas further refluxed with heating for 2 hr. The reaction mixture wascooled to room temperature, water was added, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel chromatography [eluent: hexane/ethyl acetate=50/50→25/75(volume ratio)] to give the title compound as a colorless amorphouscompound (0.20 g, 12%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.2 Hz, 3H), 1.18 (d, J=6.0 Hz,3H), 1.23-2.23 (m, 10H), 2.78-3.08 (m, 4H), 3.33 (s, 3H), 3.75 (br s,1H), 4.03 (s, 2H), 4.10-4.25 (m, 1H), 5.01-5.12 (m, 1H), 7.36-7.50 (m,6H), 7.59-7.65 (m, 1H), 7.72-7.75 (m, 1H), 7.93 (s, 1H).

Reference Example 4494′-({4-[cis-4-(2-hydroxy-2-methylpropyl)-4-methoxycyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-({4-[cis-4-(2-hydroxypropyl)-4-methoxycyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(200 mg) in acetonitrile (5 mL) was added1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (238 mg) underice-cooling, and the mixture was stirred at room temperature for 15 hr.The reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure. Toa solution of the residue in tetrahydrofuran (5 mL) was added 1 Mmethylmagnesium bromide-tetrahydrofuran solution (0.56 mL), and themixture was stirred at room temperature for 15 hr. The reaction mixturewas diluted with saturated aqueous ammonium chloride solution, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bybasic silica gel chromatography [eluent: hexane/ethylacetate=60/40→40/60 (volume ratio)] to give the title compound as acolorless amorphous compound (79 mg, 39%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.2 Hz, 3H), 1.32 (s, 6H),1.44-1.78 (m, 8H), 2.25-2.29 (m, 2H), 2.56 (br s, 1H), 2.86-3.05 (m,4H), 3.34 (s, 3H), 3.78 (br s, 1H), 4.02 (s, 2H), 5.00-5.10 (m, 1H),7.37 (d, J=8.4 Hz, 2H), 7.38-7.44 (m, 1H), 7.46-7.49 (m, 3H), 7.59-7.65(m, 1H), 7.72-7.75 (m, 1H), 7.93 (s, 1H).

Reference Example 4504′-({4-[cis-4-(3-hydroxypropyl)-4-methoxycyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of dimethyl sulfide-borane (0.34 mL) in tetrahydrofuran (5mL) was added dropwise a solution of4′-({4-[cis-4-methoxy-4-(prop-2-en-1-yl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(1.66 g) in tetrahydrofuran (10 mL) at 0° C., and the mixture wasstirred at room temperature for 2 hr. The reaction mixture was cooled to0° C., 8N aqueous sodium hydroxide solution (2.5 mL) and then 30%aqueous hydrogen peroxide solution (3.5 mL) were added, and the mixturewas further refluxed with heating for 2 hr. The reaction mixture wascooled to room temperature, water was added, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel chromatography [eluent: hexane/ethyl acetate=50/50→25/75(volume ratio)] to give the title compound as a colorless amorphouscompound (1.39 g, 81%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.5 Hz, 3H), 1.33-1.43 (m, 2H),1.53-1.82 (m, 9H), 2.03-2.08 (m, 2H), 2.85-3.04 (m, 4H), 3.24 (s, 3H),3.63-3.69 (m, 2H), 4.02 (s, 2H), 4.96-4.57 (m, 1H), 7.35-7.49 (m, 6H),7.59-7.64 (m, 1H), 7.72-7.75 (m, 1H), 7.92 (s, 1H).

Reference Example 4513-(cis-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}-1-methoxycyclohexyl)propanoicacid

To a solution of4′-({4-[cis-4-(3-hydroxypropyl)-4-methoxycyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(1.39 g) in acetonitrile (20 mL) was added1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (1.64 g) underice-cooling, and the mixture was stirred at room temperature for 15 hr.The reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure. Toa solution of the residue in tetrahydrofuran (10 mL) was added 1 Mmethylmagnesium bromide-tetrahydrofuran solution (3.87 mL), and themixture was stirred at room temperature for 15 hr. The reaction mixturewas diluted with saturated aqueous ammonium chloride solution, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bybasic silica gel chromatography [eluent: hexane/ethylacetate=60/40-÷10/90 (volume ratio)] to give the title compound as acolorless amorphous compound (743 mg, 52%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.2 Hz, 3H), 1.32-1.43 (m, 2H),1.54-1.58 (m, 2H), 1.68-1.85 (m, 2H), 2.00-2.04 (m, 2H), 2.39-2.45 (m,2H), 2.84-3.04 (m, 2H), 3.23 (s, 3H), 4.02 (s, 2H), 4.97-5.07 (m, 1H),7.36 (d, J=8.7 Hz, 2H), 7.38-7.44 (m, 1H), 7.45-7.49 (m, 3H), 7.59-7.64(m, 1H), 7.72-7.75 (m, 1H), 7.92 (s, 1H), 8.40-9.80 (br, 1H).

Reference Example 452 methyl3-(cis-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}-1-methoxycyclohexyl)propanoate

To a mixture of3-(cis-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}-1-methoxycyclohexyl)propanoicacid (743 mg), potassium carbonate (276 mg) and acetone (5 mL) was addediodomethane (0.13 mL), and the mixture was stirred at room temperaturefor 12 hr. 1 N Hydrochloric acid was added to the reaction mixture, andthe mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel chromatography [eluent: hexane/ethylacetate=70/30→50/50 (volume ratio)] to give the title compound as acolorless amorphous compound (607 mg, 80%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.2 Hz, 3H), 1.31-1.42 (m, 2H),1.53-1.83 (m, 6H), 1.98-2.02 (m, 2H), 2.34-2.39 (m, 2H), 2.84-3.04 (m,4H), 3.22 (s, 3H), 3.68 (s, 3H), 4.02 (s, 2H), 4.96-5.07 (m, 1H), 7.36(d, J=8.1 Hz, 2H), 7.38-7.44 (m, 1H), 7.45-7.49 (m, 3H), 7.59-7.64 (m,1H), 7.72-7.75 (m, 1H), 7.91 (s, 1H).

Reference Example 4534′-({4-[cis-4-(3-hydroxy-3-methylbutyl)-4-methoxycyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of methyl3-(cis-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}-1-methoxycyclohexyl)propanoate(601 mg) in tetrahydrofuran (4 mL) was added 1 M methylmagnesiumbromide-tetrahydrofuran solution (6 mL), and the mixture was stirred atroom temperature for 15 hr. The reaction mixture was diluted withsaturated aqueous ammonium chloride solution, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel chromatography [eluent: hexane/ethyl acetate=65/35→40/60(volume ratio)] to give the title compound as a colorless amorphouscompound (390 mg, 65%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.5 Hz, 3H), 1.24 (s, 6H),1.32-1.78 (m, 11H), 2.01-2.04 (m, 2H), 2.86-3.04 (m, 4H), 3.23 (s, 3H),4.02 (s, 2H), 4.96-5.07 (m, 1H), 7.36 (d, J=8.4 Hz, 2H), 7.38-7.44 (m,1H), 7.45-7.49 (m, 3H), 7.59-7.64 (m, 1H), 7.72-7.75 (m, 1H), 7.92 (s,1H).

Reference Example 454 ethyl3-[(5-methyl-4H-1,2,4-triazol-3-yl)amino]cyclobutanecarboxylate

To a solution of 5-methyl-4H-1,2,4-triazol-3-amine (16.35 g) and ethyl3-oxocyclobutanecarboxylate (12.41 g) in acetic acid (150 mL) was addedsodium triacetoxyborohydride (36.56 g), and the mixture was stirred atroom temperature for 5 days. The solvent was evaporated under reducedpressure, the residue was diluted with saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethylacetate-isopropyl alcohol (3:1). The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel chromatography [eluent: methanol/ethyl acetate=0/100-÷10/90(volume ratio)], and crystallized from diethyl ether to give the titlecompound as a colorless solid (15.93 g, 62%).

¹H NMR (300 MHz, DMSO-d₆) δ 1.17 (t, J=7.2 Hz, 3H), 1.98-2.46 (m, 7H),2.67-2.79 (m, 1H), 3.82-3.94 (m, 1H), 4.04 (q, J=7.2 Hz, 2H), 6.44 (brs, 1H), 11.60-12.60 (br, 1H).

Reference Example 455 ethyltrans-3-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclobutanecarboxylate

A solution of ethyl3-[(5-methyl-4H-1,2,4-triazol-3-yl)amino]cyclobutanecarboxylate (7.85g), ethyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate(23.15 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.62 mL) inN,N-diethylaniline (70 mL) was stirred at 180° C. for 20 hr. Thereaction mixture was diluted with ethyl acetate, and the mixture waswashed with 1 N hydrochloric acid and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gelchromatography [eluent: hexane/ethyl acetate=85/15→65/35 (volume ratio)]to give the title compound as a pale-yellow amorphous compound (1.89 g,10%).

¹H NMR (300 MHz, CDCl₃) δ 1.05 (t, J=7.2 Hz, 3H), 1.29 (t, J=7.2 Hz,3H), 1.63-1.76 (m, 2H), 2.44 (s, 3H), 2.62-2.68 (m, 2H), 2.96-3.01 (m,2H), 3.33-3.48 (m, 3H), 3.99 (s, 2H), 4.19 (q, J=7.2 Hz, 2H), 5.76-5.92(m, 1H), 7.22-7.26 (m, 2H), 7.33-7.38 (m, 1H), 7.42-7.48 (m, 2H),7.60-7.66 (m, 1H), 7.74 (d, J=7.5 Hz, 1H).

Reference Example 4564′-{[4-(trans-3-acetylcyclobutyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile

1) To a solution of ethyltrans-3-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclobutanecarboxylate(1.89 g) in tetrahydrofuran (2.5 mL)-methanol (2.5 mL) was added 2 Naqueous sodium hydroxide solution (2.5 mL), and the mixture was stirredat room temperature for 3 hr. The reaction mixture was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The extract waswashed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. To a solution of theobtained residue, N,O-dimethylhydroxylamine hydrochloride (488 mg),triethylamine (506 mg) and 1-hydroxy-1H-benzotriazole (766 mg) inacetonitrile (20 mL) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (959 mg),and the mixture was stirred at room temperature for 15 hr. Water wasadded to the reaction mixture, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel chromatography[eluent: hexane/ethyl acetate=70/30→40/60 (volume ratio)] to givecolorless amorphoustrans-3-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}-N-methoxy-N-methylcyclobutanecarboxamide(1.90 g, 97%).

2) To a solution oftrans-3-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}-N-methoxy-N-methylcyclobutanecarboxamide(1.90 g) in tetrahydrofuran (5 mL) was added 1 M methylmagnesiumbromide-tetrahydrofuran solution (5.3 mL), and the mixture was stirredat room temperature for 3 hr. The reaction mixture was diluted withsaturated aqueous ammonium chloride solution, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel chromatography [eluent: hexane/ethyl acetate=70/30→50/50(volume ratio)] to give the title compound as a colorless amorphouscompound (1.38 g, 79%).

¹H NMR (300 MHz, CDCl₃) δ 1.04 (t, J=7.2 Hz, 3H), 1.63-1.76 (m, 2H),2.18 (s, 3H), 2.44 (s, 3H), 2.59-2.67 (m, 2H), 2.95-3.01 (m, 2H),3.28-3.39 (m, 2H), 3.50-3.59 (m, 1H), 3.99 (s, 2H), 5.55-5.67 (m, 1H),7.22-7.47 (m, 5H), 7.60-7.66 (m, 1H), 7.73-7.75 (m, 1H).

Reference Example 4573′-fluoro-4′-{[4-(trans-3-hydroxycyclobutyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

To a mixture of4′-{[4-(trans-3-acetylcyclobutyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile(1.38 g), 30% aqueous hydrogen peroxide solution (13.85 mL) andchloroform (20 mL) was added trifluoroacetic acid anhydride (7.66 mL),and the mixture was stirred at 60° C. for 15 hr. The reaction mixturewas cooled to room temperature, saturated aqueous sodium hydrogencarbonate solution and sodium thiosulfate were added, and the mixturewas extracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. To a solution of the obtained residuein tetrahydrofuran (3 mL)-methanol (3 mL) was added 2 N aqueous sodiumhydroxide solution (2 mL), and the mixture was stirred at roomtemperature for 1 hr. The reaction mixture was acidified with 1 Nhydrochloric acid, and extracted with ethyl acetate. The extract waswashed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue waspurified by basic silica gel chromatography [eluent: hexane/ethylacetate=60/40→35/65 (volume ratio)] to give the title compound as acolorless amorphous compound (0.90 g, 69%).

¹H NMR (300 MHz, CDCl₃) δ 1.04 (t, J=7.2 Hz, 3H), 1.63-1.75 (m, 2H),1.78 (br s, 1H), 2.35-2.43 (m, 2H), 2.44 (s, 3H), 2.95-3.00 (m, 2H),3.35-3.45 (m, 2H), 4.00 (s, 2H), 4.85 (br s, 1H), 5.84-5.95 (m, 1H),7.22-7.26 (m, 2H), 7.34 (d, J=7.8 Hz, 1H), 7.41-7.48 (m, 2H), 7.60-7.66(m, 1H), 7.73-7.76 (m, 1H).

Reference Example 458 ethyl[(trans-3-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclobutyl)oxy]acetate

To a mixture of3′-fluoro-4′-{[4-(trans-3-hydroxycyclobutyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(899 mg), rhodium(II) acetate (dimer) (42 mg) and toluene (20 mL) wasadded dropwise ethyl diazoacetate (464 μL) under an argon atmosphere at70° C., and the mixture was stirred at 70° C. for 1 hr. The reactionmixture was concentrated under reduced pressure, and the residue waspurified by silica gel chromatography [eluent: hexane/ethylacetate=70/30→55/45 (volume ratio)] to give the title compound as acolorless amorphous compound (557 mg, 53%).

¹H NMR (300 MHz, CDCl₃) δ 1.04 (t, J=7.2 Hz, 3H), 1.30 (t, J=7.2 Hz,3H), 1.63-1.75 (m, 2H), 2.43 (s, 3H), 2.49-2.58 (m, 2H), 2.95-3.00 (m,2H), 3.25-3.35 (m, 2H), 3.99 (s, 2H), 4.04 (s, 2H), 4.23 (q, J=7.2 Hz,2H), 4.54-4.61 (m, 1H), 5.77-5.89 (m, 1H), 7.22-7.26 (m, 2H), 7.31-7.36(m, 1H), 7.41-7.48 (m, 2H), 7.60-7.66 (m, 1H), 7.73-7.76 (m, 1H).

Reference Example 4593′-fluoro-4′-({4-[trans-3-(2-hydroxy-2-methylpropoxy)cyclobutyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of ethyl[(trans-3-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclobutyl)oxy]acetate(557 mg) in tetrahydrofuran (5 mL) was added 1 M methylmagnesiumbromide-tetrahydrofuran solution (5 mL), and the mixture was stirred atroom temperature for 15 hr. The reaction mixture was diluted withsaturated aqueous ammonium chloride solution, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel chromatography [eluent: hexane/ethyl acetate=65/35→40/60(volume ratio)] to give the title compound as a colorless amorphouscompound (437 mg, 80%).

¹H NMR (300 MHz, CDCl₃) δ 1.04 (t, J=7.2 Hz, 3H), 1.24 (s, 6H),1.63-1.76 (m, 2H), 2.32 (s, 1H), 2.37-2.48 (m, 2H), 2.44 (s, 3H),2.95-3.01 (m, 2H), 3.20 (s, 2H), 3.26-3.36 (m, 2H), 4.00 (s, 2H),4.40-4.45 (m, 1H), 5.75-5.86 (m, 1H), 7.22-7.26 (m, 2H), 7.35 (t, J=10.8Hz, 1H), 7.41-7.48 (m, 2H), 7.60-7.66 (m, 1H), 7.73-7.76 (m, 1H).

Reference Example 460 ethylcis-3-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclobutanecarboxylate

A solution of ethyl3-[(5-methyl-4H-1,2,4-triazol-3-yl)amino]cyclobutanecarboxylate (7.85g), ethyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate(23.15 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.62 mL) inN,N-diethylaniline (70 mL) was stirred at 180° C. for 20 hr. Thereaction mixture was diluted with ethyl acetate, and the mixture waswashed with 1 N hydrochloric acid and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gelchromatography [eluent: hexane/ethyl acetate=85/15→65/35 (volume ratio)]to give the title compound as a pale-yellow amorphous compound (3.91 g,21%).

¹H NMR (300 MHz, CDCl₃) δ 1.04 (t, J=7.2 Hz, 3H), 1.29 (t, J=7.2 Hz,3H), 1.63-1.75 (m, 2H), 2.43 (s, 3H), 2.63-2.72 (m, 2H), 2.82-3.00 (m,3H), 3.36-3.46 (m, 2H), 3.99 (s, 2H), 4.19 (q, J=7.2 Hz, 2H), 5.24-5.36(m, 1H), 7.22-7.26 (m, 2H), 7.35 (d, J=7.8 Hz, 1H), 7.41-7.48 (m, 2H),7.60-7.66 (m, 1H), 7.73-7.76 (m, 1H).

Reference Example 461

cis-3-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}-N-methoxy-N-methylcyclobutanecarboxamide

To a solution of ethylcis-3-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclobutanecarboxylate(3.91 g) in tetrahydrofuran (5.5 mL)-methanol (5.5 mL) was added 2 Naqueous sodium hydroxide solution (5.5 mL), and the mixture was stirredat room temperature for 3 hr. The reaction mixture was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The extract waswashed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. To a solution of theobtained residue, N,O-dimethylhydroxylamine hydrochloride (1.07 g),triethylamine (1.11 g) and 1-hydroxy-1H-benzotriazole (1.68 g) inacetonitrile (40 mL) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.11 g),and the mixture was stirred at room temperature for 15 hr. Water wasadded to the reaction mixture, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel chromatography[eluent: hexane/ethyl acetate=70/30→40/60 (volume ratio)] to give thetitle compound as a colorless amorphous compound (3.65 g, 91%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.2 Hz, 3H), 1.63-1.73 (m, 3H),2.43 (s, 3H), 2.65-2.73 (m, 2H), 2.94-2.99 (m, 2H), 3.20 (s, 3H),3.20-3.38 (m, 2H), 3.68 (s, 3H), 3.99 (s, 2H), 5.12-5.24 (m, 1H),7.21-7.48 (m, 5H), 7.60-7.66 (m, 1H), 7.73-7.76 (m, 1H).

Reference Example 4624′-{[4-(cis-3-acetylcyclobutyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile

To a solution ofcis-3-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}-N-methoxy-N-methylcyclobutanecarboxamide(3.65 g) in tetrahydrofuran (10 mL) was added 1 M methylmagnesiumbromide-tetrahydrofuran solution (10 mL), and the mixture was stirred atroom temperature for 3 hr. The reaction mixture was diluted withsaturated aqueous ammonium chloride solution, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel chromatography [eluent: hexane/ethyl acetate=70/30→50/50(volume ratio)] to give the title compound as a colorless amorphouscompound (2.83 g, 85%).

¹H NMR (300 MHz, CDCl₃) δ 1.04 (t, J=7.2 Hz, 3H), 1.62-1.73 (m, 2H),2.24 (s, 3H), 2.42 (s, 3H), 2.57-2.67 (m, 2H), 2.89-3.01 (m, 3H),3.33-3.44 (m, 2H), 3.98 (s, 2H), 5.36-5.47 (m, 1H), 7.22-7.48 (m, 5H),7.60-7.66 (m, 1H), 7.73-7.76 (m, 1H).

Reference Example 4633′-fluoro-4′-{[4-(cis-3-hydroxycyclobutyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

To a mixture of4′-{[4-(cis-3-acetylcyclobutyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile(2.83 g), 30% aqueous hydrogen peroxide solution (28.5 mL) andchloroform (30 mL) was added trifluoroacetic acid anhydride (15.75 mL),and the mixture was stirred at 60° C. for 15 hr. The reaction mixturewas cooled to room temperature, saturated aqueous sodium hydrogencarbonate solution and sodium thiosulfate were added, and the mixturewas extracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. To a solution of the obtained residuein tetrahydrofuran (5 mL)-methanol (5 mL) was added 2 N aqueous sodiumhydroxide solution (4 mL), and the mixture was stirred at roomtemperature for 1 hr. The reaction mixture was acidified with 1 Nhydrochloric acid, and extracted with ethyl acetate. The extract waswashed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue waspurified by basic silica gel chromatography [eluent: hexane/ethylacetate=60/40→35/65 (volume ratio)] to give the title compound as acolorless amorphous compound (1.70 g, 63%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.5 Hz, 3H), 1.65-1.78 (m, 2H),2.48 (s, 3H), 2.86-3.06 (m, 6H), 4.00 (s, 2H), 4.11-4.21 (m, 1H), 5.11(d, J=11.4 Hz, 1H), 5.46-5.57 (m, 1H), 7.22-7.26 (m, 2H), 7.36 (d, J=7.5Hz, 1H), 7.41-7.47 (m, 2H), 7.60-7.66 (m, 1H), 7.73-7.75 (m, 1H).

Reference Example 464 ethyl[(cis-3-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclobutyl)oxy]acetate

To a mixture of3′-fluoro-4′-{[4-(cis-3-hydroxycyclobutyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(1.70 g), rhodium(II) acetate (dimer) (80 mg) and toluene (40 mL) wasadded dropwise ethyl diazoacetate (0.88 mL) under an argon atmosphere at70° C., and the mixture was stirred at 70° C. for 1 hr. The reactionmixture was concentrated under reduced pressure, and the residue waspurified by silica gel chromatography [eluent: hexane/ethylacetate=70/30→55/45 (volume ratio)] to give the title compound as acolorless amorphous compound (895 mg, 45%).

¹H NMR (300 MHz, CDCl₃) δ 1.04 (t, J=7.2 Hz, 3H), 1.29 (t, J=7.2 Hz,3H), 1.65-1.76 (m, 2H), 2.44 (s, 3H), 2.68-2.78 (m, 2H), 2.95-3.01 (m,2H), 3.26-3.37 (m, 2H), 3.99 (s, 2H), 4.14 (s, 2H), 4.23 (q, J=7.2 Hz,2H), 4.93-5.05 (m, 1H), 7.22-7.26 (m, 2H), 7.33-7.38 (m, 1H), 7.41-7.48(m, 2H), 7.60-7.66 (m, 1H), 7.73-7.76 (m, 1H).

Reference Example 4653′-fluoro-4′-({4-[cis-3-(2-hydroxy-2-methylpropoxy)cyclobutyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of ethyl[(cis-3-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclobutyl)oxy]acetate(895 mg) in tetrahydrofuran (8 mL) was added 1 M methylmagnesiumbromide-tetrahydrofuran solution (8 mL), and the mixture was stirred atroom temperature for 15 hr. The reaction mixture was diluted withsaturated aqueous ammonium chloride solution, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel chromatography [eluent: hexane/ethyl acetate=65/35→40/60(volume ratio)] to give the title compound as a colorless amorphouscompound (606 mg, 70%).

¹H NMR (300 MHz, CDCl₃) δ 1.04 (t, J=7.5 Hz, 3H), 1.24 (s, 6H),1.63-1.76 (m, 2H), 2.44 (s, 3H), 2.67-2.76 (m, 2H), 2.81 (br s, 1H),2.95-3.01 (m, 2H), 3.19-3.29 (m, 2H), 3.25 (s, 2H), 3.87-3.96 (m, 1H),3.99 (s, 2H), 5.08-5.20 (m, 1H), 7.22-7.25 (m, 2H), 7.35 (t, J=10.8 Hz,1H), 7.41-7.47 (m, 2H), 7.60-7.65 (m, 1H), 7.73-7.76 (m, 1H).

Reference Example 466 ethyl2-[(cis-3-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclobutyl)oxy]propanoate

To a mixture of3′-fluoro-4′-{[4-(cis-3-hydroxycyclobutyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(659 mg), rhodium(II) acetate (dimer) (31 mg) and methylene chloride (5mL) was added dropwise ethyl 2-diazopropanoate (359 mg) under an argonatmosphere at 70° C., and the mixture was stirred at room temperaturefor 2 hr. The reaction mixture was concentrated under reduced pressure,and the residue was purified by basic silica gel chromatography [eluent:hexane/ethyl acetate=90/10→70/30 (volume ratio)] to give the titlecompound as a colorless amorphous compound (553 mg, 69%).

¹H NMR (300 MHz, CDCl₃) δ 1.04 (t, J=7.2 Hz, 3H), 1.29 (t, J=7.2 Hz,3H), 1.44 (d, J=6.9 Hz, 3H), 1.63-1.75 (m, 2H), 2.43 (s, 3H), 2.69-2.77(m, 2H), 2.95-3.00 (m, 2H), 3.16-3.33 (m, 2H), 3.87-3.96 (m, 1H), 3.98(s, 2H), 4.08 (d, J=6.9 Hz, 1H), 4.20 (q, J=7.2 Hz, 2H), 4.85-4.97 (m,1H), 7.21-7.26 (m, 2H), 7.32-7.37 (m, 1H), 7.41-7.47 (m, 2H), 7.60-7.65(m, 1H), 7.72-7.75 (m, 1H).

Reference Example 4673′-fluoro-4′-({4-[cis-3-(2-hydroxy-1,2-dimethylpropoxy)cyclobutyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of ethyl2-[(cis-3-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclobutyl)oxy]propanoate(553 mg) in tetrahydrofuran (5 mL) was added 1 M methylmagnesiumbromide-tetrahydrofuran solution (5 mL), and the mixture was stirred atroom temperature for 15 hr. The reaction mixture was diluted withsaturated aqueous ammonium chloride solution, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel chromatography [eluent: hexane/ethyl acetate=80/20→60/40(volume ratio)] to give the title compound as a colorless amorphouscompound (430 mg, 79%).

¹H NMR (300 MHz, CDCl₃) δ 1.04 (t, J=7.5 Hz, 3H), 1.11 (d, J=6.3 Hz,3H), 1.18 (s, 3H), 1.20 (s, 3H), 1.63-1.75 (m, 2H), 2.46 (s, 3H),2.62-2.80 (m, 2H), 2.96-3.01 (m, 2H), 3.20-3.34 (m, 2H), 3.40-3.70 (br,1H), 3.99 (s, 2H), 3.99-4.08 (m, 1H), 5.24-5.36 (m, 1H), 7.22-7.26 (m,2H), 7.35 (d, J=7.8 Hz, 1H), 7.41-7.47 (m, 2H), 7.60-7.66 (m, 1H),7.73-7.76 (m, 1H).

Reference Example 4684′-{[4-(5-methyl-6,13-dioxadispiro[3.2.5.2]tetradec-10-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(12.67 g), 1-[1-(hydroxymethyl)cyclobutyl]ethanol (4.26 g),p-toluenesulfonic acid hydrate (0.57 g) and toluene (300 mL) wasrefluxed with heating for 5 hr while dehydrating with a Dean-Stark trap.The reaction mixture was cooled to room temperature, and diluted withethyl acetate, and the mixture was washed with saturated aqueous sodiumhydrogen carbonate solution and saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel chromatography[eluent: hexane/ethyl acetate=80/20→40/60 (volume ratio)] to give thetitle compound as a colorless amorphous compound (13.64 g, 87%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.5 Hz, 3H), 1.26-1.45 (m, 5H),1.57-1.90 (m, 10H), 2.18-2.30 (m, 1H), 2.74-3.04 (m, 5H), 3.68-3.92 (m,3H), 4.01 (s, 2H), 5.03-5.13 (m, 1H), 7.36 (d, J=7.5 Hz, 2H), 7.38-7.44(m, 1H), 7.45-7.48 (m, 3H), 7.59-7.64 (m, 1H), 7.72-7.75 (m, 1H), 7.89(s, 0.4H), 7.92 (s, 0.6H).

Reference Example 4694′-[(4-{4-[1-(1-formylcyclobutyl)ethoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

A mixture of4′-{[4-(5-methyl-6,13-dioxadispiro[3.2.5.2]tetradec-10-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(15.33 g), sodium cyanotrihydroborate (7.01 g), anhydrous magnesiumsulfate (12.76 g) and tetrahydrofuran (330 mL) was stirred at roomtemperature for 10 min. Then, boron trifluoride-diethyl ether complex(13.4 mL) was added dropwise, and the mixture was stirred under an argonatmosphere at 50° C. for 8 hr. The reaction mixture was cooled to roomtemperature, saturated aqueous sodium hydrogen carbonate solution wasadded, and the mixture was extracted with ethyl acetate. The extract waswashed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. To a solution of theobtained residue in acetonitrile (300 mL) was added1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (1.64 g) underice-cooling, and the mixture was stirred at room temperature for 15 hr.The reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel chromatography [eluent:hexane/ethyl acetate=80/20→50/50 (volume ratio)] to give the titlecompound as a colorless amorphous compound (7.21 g, 47%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.2 Hz, 3H), 1.10 (d, J=6.3 Hz,3H), 1.39-2.34 (m, 14H), 2.60-2.80 (m, 1H), 2.95-3.11 (m, 3H), 3.44-3.71(m, 1H), 3.81 (q, J=6.3 Hz, 1H), 4.02 (s, 2H), 5.03-5.10 (m, 1H),7.35-7.49 (m, 6H), 7.59-7.65 (m, 1H), 7.72-7.75 (m, 1H), 7.88 (s, 0.6H),7.91 (s, 0.4H), 9.73 (s, 0.4H), 9.91 (s, 0.6H).

Reference Example 4704′-[(4-{4-[1-(1-acetylcyclobutyl)ethoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

To a solution of4′-[(4-{4-[1-(1-formylcyclobutyl)ethoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(10.35 g) in tetrahydrofuran (50 mL) was added 1 M methylmagnesiumbromide-tetrahydrofuran solution (27 mL), and the mixture was stirred atroom temperature for 15 hr. 1 N Hydrochloric acid was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure. Toa solution of the residue in acetonitrile (200 mL) was added1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (8.48 g), and themixture was stirred at room temperature for 2 hr. Saturated aqueoussodium hydrogen carbonate solution was added to the reaction mixture,and the mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel chromatography [eluent: hexane/ethylacetate=80/20→60/40 (volume ratio)] to give the title compound as acolorless amorphous compound (8.32 g, 79%).

¹H NMR (300 MHz, CDCl₃) δ 1.00-1.08 (m, 6H), 1.25-2.39 (m, 17H),2.64-2.80 (m, 1H), 2.99-3.12 (m, 3H), 3.45-3.69 (m, 1H), 3.73-3.81 (m,1H), 4.01 (s, 2H), 5.03-5.13 (m, 1H), 7.36 (d, J=7.8 Hz, 2H), 7.38-7.44(s, 1H), 7.46-7.49 (m, 3H), 7.59-7.64 (m, 1H), 7.73 (d, J=7.8 Hz, 1H),7.83 (s, 0.6H), 7.91 (s, 0.4H).

Reference Example 4714′-[(4-{trans-4-[1-(1-hydroxycyclobutyl)ethoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

To a mixture of4′-[(4-{4-[1-(1-acetylcyclobutyl)ethoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(9.20 g), 30% aqueous hydrogen peroxide solution (77.5 mL) andchloroform (80 mL) was added trifluoroacetic acid anhydride (42.8 mL),and the mixture was stirred at 60° C. for 15 hr. The reaction mixturewas cooled to room temperature, saturated aqueous sodium hydrogencarbonate solution and 1 M sodium thiosulfate were added, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. To a solution of the obtainedresidue in tetrahydrofuran (15 mL)-methanol (15 mL) was added 2 Naqueous sodium hydroxide solution (15 mL), and the mixture was stirredat room temperature for 2 hr. The reaction mixture was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The extract waswashed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel chromatography [eluent: hexane/ethylacetate=80/20→40/60 (volume ratio)] to give the title compound as acolorless amorphous compound (1.45 g, 17%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.2 Hz, 3H), 1.16 (d, J=6.0 Hz,3H), 1.38-1.60 (m, 3H), 1.66-1.84 (m, 4H), 2.00-2.18 (m, 6H), 2.64-2.78(m, 2H), 3.00-3.06 (m, 4H), 3.48-3.60 (m, 2H), 4.01 (s, 2H), 5.02-5.10(m, 1H), 7.36 (d, J=8.1 Hz, 2H), 7.39-7.44 (m, 1H), 7.47-7.49 (m, 3H),7.59-7.65 (m, 1H), 7.72-7.75 (m, 1H), 7.92 (s, 1H).

Reference Example 4724′-[(4-{cis-4-[1-(1-hydroxycyclobutyl)ethoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

To a mixture of4′-[(4-{4-[1-(1-acetylcyclobutyl)ethoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(9.20 g), 30% aqueous hydrogen peroxide solution (77.5 mL) andchloroform (80 mL) was added trifluoroacetic acid anhydride (42.8 mL),and the mixture was stirred at 60° C. for 15 hr. The reaction mixturewas cooled to room temperature, saturated aqueous sodium hydrogencarbonate solution and 1 M sodium thiosulfate were added, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. To a solution of the obtainedresidue in tetrahydrofuran (15 mL)-methanol (15 mL) was added 2 Naqueous sodium hydroxide solution (15 mL), and the mixture was stirredat room temperature for 2 hr. The reaction mixture was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The extract waswashed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel chromatography [eluent: hexane/ethylacetate=80/20→40/60 (volume ratio)] to give the title compound as acolorless amorphous compound (0.50 g, 6%).

¹H NMR (300 MHz, CDCl₃) δ 1.05 (t, J=7.2 Hz, 3H), 1.20 (d, J=6.0 Hz,3H), 1.42-2.05 (m, 14H), 2.85-3.11 (m, 4H), 3.56 (q, J=6.0 Hz, 1H),3.74-3.80 (m, 2H), 4.02 (s, 2H), 5.10-5.19 (m, 1H), 7.37 (d, J=8.4 Hz,2H), 7.39-7.44 (m, 1H), 7.46-7.49 (m, 3H), 7.59-7.64 (m, 1H), 7.72-7.75(m, 1H), 7.93 (s, 1H).

Reference Example 4734′-({4-[4-(2-hydroxy-1,1,2-trimethylpropoxy)phenyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of methyl2-(4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}phenoxy)-2-methylpropanoate(1.0 g) in tetrahydrofuran (9 mL) was added dropwise methylmagnesiumbromide (1 M tetrahydrofuran solution, 1.8 mL) at 0° C., and the mixturewas stirred for 3 hr. Ethyl acetate and then saturated aqueous ammoniumchloride solution were added. The mixture was extracted with ethylacetate, and the organic layer was washed with saturated brine, driedover anhydrous magnesium sulfate, and concentrated. The residue waspurified by silica gel column chromatography to give the title compoundas a pale-yellow amorphous solid (0.98 g, 98%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.11 (t, J=7.4 Hz, 3H), 1.33 (s, 6H),1.34 (s, 6H), 1.72-1.88 (m, 2H), 2.67 (s, 1H), 3.13 (dd, J=10.2, 5.7 Hz,2H), 4.07 (s, 2H), 7.10-7.91 (m, 13H)

Reference Example 4744′-({4-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of methyl2-(4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}phenoxy)-2-methylpropanoate(2.0 g) in tetrahydrofuran (16 mL) was added lithium borohydride (0.49g) and the mixture was stirred for 18 hr. Ethyl acetate and thensaturated aqueous ammonium chloride solution were added. The mixture wasextracted with ethyl acetate, and the organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (0.97 g, 51%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.11 (t, J=7.4 Hz, 3H), 1.35 (s, 6H),1.70-1.88 (m, J=15.4, 7.6, 7.4, 7.4 Hz, 2H), 2.19 (t, J=6.6 Hz, 1H),3.13 (dd, J=10.4, 5.5 Hz, 2H), 3.62 (d, J=6.4 Hz, 2H), 4.07 (s, 2H),7.10-7.92 (m, 13H)

Reference Example 4754′-({4-[4-(1,1-dimethyl-2-oxoethoxy)phenyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-({4-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.97 g) in methylene chloride (10 mL) was added1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (2.3 g),and the mixture was stirred for 3 hr. Ethyl acetate, water and sodiumthiosulfate were added to the reaction mixture, and the mixture wasstirred for 30 min, and extracted with ethyl acetate. The organic layerwas washed with saturated brine and dried over anhydrous magnesiumsulfate, and the solvent was evaporated. The residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.97 g, 99%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.11 (t, J=7.3 Hz, 3H), 1.50 (s, 6H),1.69-1.89 (m, J=15.3, 7.6, 7.4, 7.4 Hz, 2H), 3.04-3.21 (m, 2H), 4.06 (s,2H), 6.93-7.93 (m, 13H), 9.84 (s, 1H)

Reference Example 4764′-({4-[4-(2-hydroxy-1,1-dimethylpropoxy)phenyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-({4-[4-(1,1-dimethyl-2-oxoethoxy)phenyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.97 g) in tetrahydrofuran (10 mL) was added dropwise methylmagnesiumbromide (1 M tetrahydrofuran solution, 0.91 mL) at 0° C., and themixture was stirred for 3 hr. Ethyl acetate and then saturated aqueousammonium chloride solution were added. The mixture was extracted withethyl acetate, and the organic layer was washed with saturated brine,dried over anhydrous magnesium sulfate, and concentrated. The residuewas purified by silica gel column chromatography to give the titlecompound as a pale-yellow amorphous solid (0.72 g, 72%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.11 (t, J=7.4 Hz, 3H), 1.23 (d, J=6.4Hz, 3H), 1.29 (s, 6H), 1.71-1.89 (m, 2H), 2.61 (d, J=3.4 Hz, 1H),3.08-3.18 (m, 2H), 3.84-3.94 (m, 1H), 4.07 (s, 2H), 7.08-7.91 (m, 13H)

Reference Example 477 4′-(1-hydroxyethyl)biphenyl-2-carbonitrile

To a solution of 4′-formylbiphenyl-2-carbonitrile (10.00 g) intetrahydrofuran (100 mL) was slowly added dropwise a 1 M solution (50mL) of methylmagnesium bromide in tetrahydrofuran at 0° C., and themixture was stirred at room temperature for 2 hr. The reaction mixturewas poured into 1 M hydrochloric acid (60 mL), and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as apale-yellow oil (10.03 g, 93%).

¹H NMR (300 MHz, CDCl₃) δ 1.55 (d, J=6.6, 3H), 1.88 (d, J=3.6, 1H),4.92-5.03 (m, 1H), 7.39-7.58 (m, 6H), 7.60-7.67 (m, 1H), 7.73-7.78 (m,1H)

Reference Example 478 4′-(1-bromoethyl)biphenyl-2-carbonitrile

To a solution (15 mL) of 4′-(1-hydroxyethyl)biphenyl-2-carbonitrile(3.52 g) in toluene was added phosphine tribromide (5.00 g) at roomtemperature, and the mixture was stirred at room temperature overnight.The reaction mixture was concentrated, and the residue was dissolved inethyl acetate. The obtained ethyl acetate solution was washed withsaturated aqueous sodium hydrogen carbonate and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as apale-yellow oil (3.93 g, 87%).

¹H NMR (300 MHz, CDCl₃) δ 2.09 (d, J=6.9, 3H), 5.26 (q, J=6.9, 1H),7.40-7.68 (m, 7H), 7.72-7.78 (m, 1H)

Reference Example 479N-[(2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]-3-methyl-1H-1,2,4-triazol-5-amine

To a solution of 3-methyl-1H-1,2,4-triazol-5-amine (1.6 g) in aceticacid (30 mL) was added (2R,6S)-2,6-dimethyltetrahydro-4H-pyran-4-one(2.5 g) at room temperature, and the mixture was stirred for 30 min.Sodium triacetoxyborohydride (5.2 g) was added, and the mixture wasstirred at room temperature for 20 hr. Acetic acid was evaporated andethyl acetate and water were added to the residue. The mixture wasneutralized with sodium hydrogen carbonate, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was dissolved in a small amount of ethylacetate, and the mixture was crystallized from diisopropyl ether. Theresulting solid was collected by filtration, washed with diisopropylether, and dried by heating under reduced pressure to give the titlecompound as a pale-yellow solid (0.75 g, 22%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.16-1.24 (m, 6H), 1.44-2.13 (m, 4H),2.34 (s, 3H), 3.49-4.93 (m, 4H), 9.30-10.92 (m, 1H)

Reference Example 480N-[(2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]-1H-1,2,4-triazol-5-amine

To a solution of 1H-1,2,4-triazol-5-amine (1.6 g) in acetic acid (30 mL)was added (2R,6S)-2,6-dimethyltetrahydro-4H-pyran-4-one (2.5 g) at roomtemperature, and the mixture was stirred for 30 min. After stirring,sodium triacetoxyborohydride (5.2 g) was added, and the mixture wasstirred at room temperature for 20 hr. Acetic acid was evaporated andethyl acetate and water were added to the residue. The mixture wasneutralized with sodium hydrogen carbonate, and extracted with ethylacetate. The organic layer was washed with water and saturated brine,dried over anhydrous magnesium sulfate, and concentrated. The residuewas dissolved in a small amount of ethyl acetate, and the mixture wascrystallized from diisopropyl ether. The resulting solid was collectedby filtration, washed with diisopropyl ether, and dried by heating underreduced pressure to give the title compound as a pale-yellow solid (1.6g, 49%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91-1.13 (m, 7H), 1.22-1.36 (m, 1H),1.63-1.93 (m, 2H), 3.37-3.84 (m, 3H), 5.87-8.13 (m, 2H), 11.62-12.91 (m,1H)

Reference Example 4811-benzyl-4-methyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine

To a solution (50 mL) of 1-benzyl-4-methyl-1H-pyrazol-5-amine (5 g) andtetrahydro-4H-pyran-4-one (3.2 g) in acetic acid was added sodiumcyanoborohydride (6.8 g), and the mixture was stirred at roomtemperature for 16 hr. Water was added to the reaction mixture, and thesolvent was evaporated under reduced pressure. The obtained residue waspoured into saturated aqueous sodium hydrogen carbonate, and the mixturewas extracted with ethyl acetate. The obtained extract was dried overanhydrous sodium sulfate, the solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (1.9 g,38%).

¹H NMR (300 MHz, DMSO-d₆) δ 1.24-1.41 (m, 2H) 1.55-1.67 (m, 2H) 1.92 (s,3H) 2.78-2.93 (m, 1H) 3.01-3.14 (m, 2H) 3.76 (dd, J=8.2, 2.7 Hz, 2H)4.42 (d, J=8.7 Hz, 1H) 5.16 (s, 2H) 7.06-7.14 (m, 3H) 7.19-7.33 (m, 3H)

Reference Example 4824-methyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine

A mixture of1-benzyl-4-methyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine (1.9g), activated carbon-supported 20 mass % palladium hydroxide (0.6 g) andformic acid (20 mL) was stirred at room temperature for 16 hr. Theinsoluble material was filtered off through celite, and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography to give the title compound as a colorlesssolid (0.73 g, 40%).

¹H NMR (300 MHz, DMSO-d₆) δ 1.29-1.47 (m, 2H) 1.82 (s, 3H) 1.85-1.94 (m,2H) 3.25-3.50 (m, 3H) 3.79-3.90 (m, 2H) 4.37-4.50 (m, 1H) 7.13 (s, 1H)11.17 (br. s., 1H)

Reference Example 4834′-({4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.70 g) and rhodium acetate (dimer, 0.066 g) in methylene chloride (5mL) was added dropwise a solution of ethyl 2-diazopropanoate (1.0 g) inmethylene chloride (2 mL), and the mixture was stirred for 18 hr. Ethylacetate and water were added to the reaction mixture, and the mixturewas extracted with ethyl acetate. The organic layer was washed withwater and then with saturated brine, dried over anhydrous magnesiumsulfate, and concentrated. The residue was crudely purified by silicagel column chromatography. This was dissolved in tetrahydrofuran (5 mL),methylmagnesium bromide (1 M tetrahydrofuran solution, 3 mL) was addeddropwise at 0° C., and the mixture was stirred for 1 hr. The mixture wasdiluted with ethyl acetate and then saturated aqueous ammonium chloridesolution was added. The mixture was extracted with ethyl acetate, andthe organic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate, and concentrated. The residue was purified by silicagel column chromatography to give the title compound as a pale-yellowamorphous solid (0.45 g, 84%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.01-1.20 (m, 12H), 1.32-1.57 (m, 2H),1.64-1.91 (m, 4H), 2.05-2.26 (m, 2H), 2.32-2.57 (m, 3H), 3.02-3.10 (m,2H), 3.29-3.52 (m, 2H), 4.01 (s, 2H), 4.71 (br. s., 1H), 5.98 (d, J=2.3Hz, 1H), 7.34-7.77 (m, 9H)

Reference Example 484 ethyl[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate

To a solution of4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(2.63 g) and rhodium acetate (dimer, 0.12 g) in methylene chloride (20mL) was added dropwise a solution of ethyl diazoacetate (2.6 g) inmethylene chloride (10 mL), and the mixture was stirred for 3 hr. Ethylacetate and water were added to the reaction mixture, and the mixturewas extracted with ethyl acetate. The organic layer was washed withwater and then with saturated brine, dried over anhydrous magnesiumsulfate, and concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (2.17 g, 70%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.05 (t, J=7.4 Hz, 3H), 1.30 (t, J=7.2Hz, 3H), 1.41-1.93 (m, 6H), 2.16-2.56 (m, 4H), 3.01-3.10 (m, 2H),3.39-3.53 (m, 1H), 4.00 (s, 2H), 4.13 (s, 2H), 4.23 (q, J=6.9 Hz, 2H),4.73 (br. s., 1H), 5.97 (d, J=2.3 Hz, 1H), 7.31-7.79 (m, 9H)

Reference Example 4854′-({4-[trans-4-(2-hydroxyethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of ethyl[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate(1.16 g) in tetrahydrofuran (8 mL)-ethanol (2 mL) was added lithiumborohydride (0.46 g), and the mixture was stirred for 18 hr. To thereaction mixture were added ethyl acetate and saturated aqueous ammoniumchloride solution, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and then with saturated brine, driedover anhydrous magnesium sulfate, and concentrated. The residue waspurified by silica gel column chromatography to give the title compoundas a pale-yellow amorphous solid (0.64 g, 60%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.3 Hz, 3H), 1.37-1.54 (m,2H), 1.64-1.91 (m, 4H), 2.00 (t, J=6.1 Hz, 1H), 2.15-2.55 (m, 4H),3.00-3.10 (m, 2H), 3.33-3.46 (m, 1H), 3.58-3.64 (m, 2H), 3.70-3.77 (m,2H), 4.01 (s, 2H), 4.53-4.98 (m, 1H), 5.98 (d, J=2.3 Hz, 1H), 7.34-7.77(m, 9H)

Reference Example 4862-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide

To a solution of ethyl[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate(1.17 g) in tetrahydrofuran (10 mL) was added 1 M aqueous sodiumhydroxide solution (10 mL), and the mixture was stirred at 50° C. for 15hr. The mixture was allowed to cool, and neutralized with 1 Mhydrochloric acid, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and then with saturated brine, driedover anhydrous magnesium sulfate, and concentrated. The residue wasdissolved in acetonitrile (20 mL), methoxymethylamine hydrochloride(0.62 g), 4-dimethylaminopyridine (0.078 g), diisopropylethylamine (1.9mL), 1-hydroxybenzotriazole (0.37 g) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.81 g)were added, and the mixture was stirred for 3 days. Ethyl acetate andwater were added to the reaction mixture, and the mixture was extractedwith ethyl acetate. The organic layer was washed with water and thenwith saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (0.65 g, 54%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.4 Hz, 3H), 1.44-1.90 (m,6H), 2.22-2.54 (m, 4H), 3.01-3.10 (m, 2H), 3.20 (s, 3H), 3.42-3.58 (m,1H), 3.70 (s, 3H), 4.01 (s, 2H), 4.33 (s, 2H), 4.59-5.09 (m, 1H), 5.98(d, J=2.3 Hz, 1H), 7.32-7.79 (m, 9H)

Reference Example 4874′-({4-[trans-4-(2-hydroxypropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide(0.65 g) in tetrahydrofuran (6 mL) was added dropwise methylmagnesiumbromide (1 M tetrahydrofuran solution, 2.3 mL) at 0° C., and the mixturewas stirred for 1 hr. Ethyl acetate and then saturated aqueous ammoniumchloride solution were added. The mixture was extracted with ethylacetate, and the organic layer was washed with saturated brine, driedover anhydrous magnesium sulfate, and concentrated. The residue wasdissolved in ethanol (6 mL), and sodium borohydride (0.044 g) was addedat 0° C. After stirring at 0° C. for 1 hr, ethyl acetate and thensaturated aqueous ammonium chloride solution were added. The mixture wasextracted with ethyl acetate, and the organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (0.57 g, 95%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.4 Hz, 3H), 1.15 (d, J=6.4Hz, 3H), 1.34-1.54 (m, 2H), 1.64-1.91 (m, 4H), 2.13-2.28 (m, 2H),2.33-2.55 (m, 3H), 3.06 (dd, J=10.4, 5.5 Hz, 2H), 3.20-3.29 (m, 1H),3.32-3.45 (m, 1H), 3.51 (dd, J=9.1, 3.0 Hz, 1H), 3.87-4.04 (m, 3H), 4.76(br. s., 1H), 5.98 (d, J=1.9 Hz, 1H), 7.33-7.77 (m, 9H)

Reference Example 4884′-({4-[trans-4-(2-cyclopropyl-2-hydroxyethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide(0.57 g) in tetrahydrofuran (6 mL) was added dropwisecyclopropylmagnesium bromide (0.5M tetrahydrofuran solution, 4 mL) at 0°C., and the mixture was stirred for 1.5 hr. To the reaction mixture wereadded ethyl acetate and then saturated aqueous ammonium chloridesolution, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, dried over anhydrous magnesiumsulfate, and concentrated. The residue was dissolved in ethanol (10 mL),sodium borohydride (0.04 g) was added, and the mixture was stirred for18 hr. To the reaction mixture were added ethyl acetate and thensaturated aqueous ammonium chloride solution, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (0.45 g, 81%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.17-0.62 (m, 4H), 0.79-0.94 (m, 1H),1.06 (t, J=7.3 Hz, 3H), 1.37-1.54 (m, 2H), 1.64-1.90 (m, 4H), 2.13-2.57(m, 5H), 2.99-3.12 (m, 3H), 3.33-3.50 (m, 2H), 3.67 (dd, J=9.4, 3.0 Hz,1H), 4.01 (s, 2H), 4.75 (br. s., 1H), 5.98 (d, J=2.3 Hz, 1H), 7.33-7.78(m, 9H)

Reference Example 4894′-({4-[trans-4-(2-hydroxy-3-methylbutoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide(0.57 g) in tetrahydrofuran (5 mL) was added dropwise isopropylmagnesiumbromide (1 M tetrahydrofuran solution, 2 mL) at 0° C., and the mixturewas stirred for 1.5 hr. To the reaction mixture were added ethyl acetateand then saturated aqueous ammonium chloride solution, and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was dissolved in ethanol (10 mL), sodiumborohydride (0.04 g) was added, and the mixture was stirred for 18 hr.To the reaction mixture were added ethyl acetate and then saturatedaqueous ammonium chloride solution, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, driedover anhydrous magnesium sulfate, and concentrated. The residue waspurified by silica gel column chromatography to give the title compoundas a pale-yellow amorphous solid (0.31 g, 56%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.92 (d, J=6.8 Hz, 3H), 0.98 (d, J=6.8Hz, 3H), 1.06 (t, J=7.3 Hz, 3H), 1.37-1.53 (m, 2H), 1.65-1.91 (m, 5H),2.14-2.55 (m, 5H), 3.01-3.11 (m, 2H), 3.31-3.63 (m, 4H), 4.01 (s, 2H),4.77 (br. s., 1H), 5.98 (d, J=2.3 Hz, 1H), 7.34-7.77 (m, 9H)

Reference Example 4904′-({5-oxo-4-[trans-4-(2-oxopropoxy)cyclohexyl]-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide(1.3 g) in tetrahydrofuran (10 mL) was added dropwise methylmagnesiumbromide (1 M tetrahydrofuran solution, 1.3 mL) at 0° C., and the mixturewas stirred for 2 hr. To the reaction mixture were added ethyl acetateand then saturated aqueous ammonium chloride solution, and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (1.12 g, 94%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.4 Hz, 3H), 1.41-1.56 (m,2H), 1.64-1.91 (m, 4H), 2.12-2.29 (m, 5H), 2.32-2.54 (m, 2H), 2.99-3.11(m, 2H), 3.31-3.50 (m, 1 H), 4.01 (s, 2H), 4.10 (s, 2H), 4.74 (br. s.,1H), 5.97 (d, J=2.3 Hz, 1H), 7.33-7.78 (m, 9H)

Reference Example 4914′-({4-[trans-4-({2-methyl-2-[(triethylsilyl)oxy]cyclopropyl]oxy)cyclohexyl}-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-({5-oxo-4-[trans-4-(2-oxopropoxy)cyclohexyl]-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(1.12 g) and triethylsilyl chloride (0.72 mL) in tetrahydrofuran (15 mL)was added dropwise lithium hexamethyldisilazide (1.1 M tetrahydrofuransolution, 2.9 mL) at −78° C., and the mixture was stirred for 2 hr. Tothe reaction mixture were added ethyl acetate and then saturated aqueoussodium hydrogen carbonate solution, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, driedover anhydrous magnesium sulfate, and concentrated. The residue wasdissolved in methylene chloride (5 mL), and the solution was addeddropwise to a solution of diethylzinc (1 M hexane solution, 15 mL) andchloroiodomethane (1.09 mL) in methylene chloride (20 mL) at 0° C., andthe mixture was stirred for 2 hr. To the reaction mixture were addedethyl acetate and then saturated aqueous ammonium chloride solution, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (0.44 g, 31%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.59-0.77 (m, 8H), 0.93-1.01 (m, 9H),1.06 (t, J=7.4 Hz, 3H), 1.28 (s, 3H), 1.39-1.56 (m, 2H), 1.66-1.88 (m,4H), 2.17-2.53 (m, 4H), 2.92-3.11 (m, 3H), 3.49-3.62 (m, 1H), 4.01 (s,2H), 4.79 (br. s., 1H), 6.01 (d, J=1.9 Hz, 1H), 7.35-7.76 (m, 9H)

Reference Example 4924′-[(4-{trans-4-[(1-{[tert-butyl(dimethyl)silyl]oxy}cyclopropyl)methoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile

To a solution of4′-({5-oxo-4-[trans-4-(2-oxopropoxy)cyclohexyl]-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.93 g) and diisopropylethylamine (0.77 mL) in methylene chloride (10mL) was added dropwise tert-butyldimethylsilyl trifluoromethanesulfonate(1.02 mL) at −78° C., and the mixture was stirred for 3 hr while warmingto 0° C. To the reaction mixture were added ethyl acetate and saturatedaqueous sodium hydrogen carbonate solution, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was crudely purified by silica gel columnchromatography, and dissolved in methylene chloride (5 mL), and themixture was added dropwise to a solution of diethylzinc (1 M hexanesolution, 7.5 mL) and chloroiodomethane (0.55 mL) in methylene chloride(10 mL) at 0° C., and the mixture was stirred for 2 hr. To the reactionmixture were added ethyl acetate and then saturated aqueous ammoniumchloride solution, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate, and concentrated. The residue was purified by silicagel column chromatography to give the title compound as a pale-yellowamorphous solid (0.67 g, 68%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.13 (s, 6H), 0.54-0.78 (m, 4 H), 0.85(s, 9H), 1.05 (t, J=7.3 Hz, 3H), 1.36-1.90 (m, 6H), 2.14-2.53 (m, 4H),3.01-3.12 (m, 2H), 3.29-3.64 (m, 3H), 4.01 (s, 2H), 4.75 (br. s., 1H),5.98 (d, J=2.1 Hz, 1H), 7.33-7.79 (m, 9H)

Reference Example 4934′-({5-oxo-7-propyl-4-[trans-4-(3,3,3-trifluoro-2-hydroxypropoxy)cyclohexyl]-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of ethyl[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate(0.75 g) and tetrabutylammonium acetate (0.042 g) in toluene (7 mL) wasadded dropwise trifluoromethanetrimethylsilyl (0.61 mL) at 0° C., andthe mixture was stirred for 3 hr. To the reaction mixture were addedethyl acetate and saturated aqueous ammonium chloride solution, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was dissolved in tetrahydrofuran (7 mL), 1 Mhydrochloric acid (7 mL) was added, and the mixture was stirred at 60°C. for 1 hr. To the reaction mixture were added ethyl acetate and then 1M aqueous sodium hydroxide solution, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, driedover anhydrous magnesium sulfate, and concentrated. The residue wasdissolved in ethanol (7 mL), sodium borohydride (0.05 g) was added at 0°C., and the mixture was stirred for 1 hr. To the reaction mixture wereadded ethyl acetate and saturated aqueous ammonium chloride solution,and the mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (0.67 g, 84%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.4 Hz, 3H), 1.26-1.75 (m, 6H),2.03-2.16 (m, 2H), 2.29-2.48 (m, 2H), 2.91-3.04 (m, 2H), 3.42-3.69 (m,3H), 3.97 (s, 2H), 4.02-4.17 (m, 1H), 4.68 (br. s., 1H), 6.33 (d, J=6.4Hz, 1H), 6.43 (d, J=2.3 Hz, 1H), 7.34-7.96 (m, 9H)

Reference Example 494trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl2-(acetyloxy)-2-methylpropanoate

To a solution of4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.47 g) in pyridine (3 mL) was added 2-chloro-1,1-dimethyl-2-oxoethylacetate (0.44 mL) and the mixture was stirred for 2 hr. Ethyl acetateand water were added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (0.47 g, 79%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.4 Hz, 3H), 1.47 (s, 6H),1.49-1.77 (m, 6H), 1.93-2.04 (m, 5H), 2.34-2.49 (m, 2H), 2.91-3.03 (m,2H), 3.98 (s, 2H), 4.55-4.90 (m, 2H), 6.54 (d, J=2.3 Hz, 1H), 7.34-7.98(m, 9H)

Reference Example 4954′-({4-[trans-4-(2-cyclopropyl-2-hydroxypropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-({5-oxo-4-[trans-4-(2-oxopropoxy)cyclohexyl]-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.30 g) in tetrahydrofuran (3 mL) was added dropwisecyclopropylmagnesium bromide (0.5M tetrahydrofuran solution, 2.3 mL) at0° C., and the mixture was stirred for 2 hr. To the reaction mixturewere added ethyl acetate and then saturated aqueous ammonium chloridesolution, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, dried over anhydrous magnesiumsulfate, and concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (0.22 g, 68%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.29-0.51 (m, 4H), 0.83-0.95 (m, 1H),1.05 (t, J=7.4 Hz, 3H), 1.10 (s, 3H), 1.35-1.54 (m, 2H), 1.65-1.90 (m,3H), 2.10 (s, 1H), 2.15-2.55 (m, 4H), 3.01-3.10 (m, 2H), 3.32-3.45 (m,3H), 4.01 (s, 2H), 4.52-4.98 (m, 1H), 5.98 (d, J=2.3 Hz, 1H), 7.34-7.78(m, 9H)

Reference Example 4964′-{[7-butyl-4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A solution of N-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazol-5-amine (2.2g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.30 mL) and methyl2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate (7.0 g) indiethylaniline (10 mL) was stirred at 180° C. for 2 hr. The mixture wasallowed to cool, ethyl acetate and water were added, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (3.6 g, 69%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.94 (t, J=7.2 Hz, 3H), 1.40-1.55 (m,2H), 1.59-1.93 (m, 8H), 2.48-2.69 (m, 2H), 3.03-3.14 (m, 2H), 3.93-4.06(m, 6H), 5.13-5.37 (m, 1H), 6.19 (d, J=2.3 Hz, 1H), 7.35-7.78 (m, 9H)

Reference Example 4974′-{[7-butyl-4-(trans-4-hydroxycyclohexyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-{[7-butyl-4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(3.6 g) in tetrahydrofuran (40 mL) was added 3M hydrochloric acid (40mL), and the mixture was stirred at 70° C. for 2 hr. The mixture wasallowed to cool, and diluted with ethyl acetate, and the mixture wasneutralized with 8M aqueous sodium hydroxide solution. The mixture wasextracted with ethyl acetate, and the organic layer was washed withwater and saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was dissolved in ethanol (20mL)-tetrahydrofuran (20 mL). Thereto was added sodium borohydride (0.26g) at 0° C. After stirring for 1 hr, ethyl acetate and saturated aqueousammonium chloride solution were added. The mixture was extracted withethyl acetate, and the organic layer was washed with water and saturatedbrine, dried over anhydrous magnesium sulfate, and concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound as a pale-yellow amorphous solid (2.9 g, 87%).

¹H NMR (300 MHz, CHLOROFORM-d) 0.94 (t, J=7.2 Hz, 3H), 1.41-1.55 (m,5H), 1.59-1.73 (m, 2H), 1.76-1.90 (m, 2H), 2.07-2.20 (m, 2H), 2.34-2.58(m, 2H), 3.01-3.13 (m, 2H), 3.67-3.85 (m, 1H), 4.01 (s, 2H), 4.49-5.04(m, 1H), 5.98 (d, J=2.3 Hz, 1H), 7.31-7.80 (m, 9H)

Reference Example 498 ethyl[(trans-4-{7-butyl-6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxopyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate

To a solution of4′-{[7-butyl-4-(trans-4-hydroxycyclohexyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(2.9 g) and rhodium acetate (dimer, 0.070 g) in methylene chloride (15mL) was added dropwise a solution of ethyl diazoacetate (3.1 mL) inmethylene chloride (3 mL), and the mixture was stirred for 3 hr. Ethylacetate and water were added to the reaction mixture, and the mixturewas extracted with ethyl acetate. The organic layer was washed withwater and then with saturated brine, dried over anhydrous magnesiumsulfate, and concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (2.1 g, 61%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.94 (t, J=7.3 Hz, 3H), 1.17-1.72 (m,9H), 1.78-1.92 (m, 2H), 2.15-2.57 (m, 4H), 3.01-3.12 (m, 2H), 3.36-3.54(m, 1H), 4.00 (s, 2H), 4.13 (s, 2H), 4.23 (q, J=7.2 Hz, 2H), 4.52-4.98(m, 1H), 5.97 (d, J=2.3 Hz, 1H), 7.31-7.78 (m, 9H)

Reference Example 4994′-({7-butyl-4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of ethyl[(trans-4-{7-butyl-6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxopyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate(0.40 g) in tetrahydrofuran (4 mL) was added dropwise methylmagnesiumbromide (1 M tetrahydrofuran solution, 0.71 mL) at 0° C., and themixture was stirred for 30 min. To the reaction mixture were added ethylacetate and then saturated aqueous ammonium chloride solution, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (0.31 g, 83%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.94 (t, J=7.2 Hz, 3H), 1.21 (s, 6H),1.36-1.54 (m, 4H), 1.58-1.72 (m, 2H), 1.77-1.91 (m, 2H), 2.13-2.27 (m,2H), 2.34-2.55 (m, 2H), 3.01-3.12 (m, 2H), 3.26-3.45 (m, 3H), 4.01 (s,2H), 4.50-5.00 (m, 1H), 5.97 (s, 1H), 7.32-7.78 (m, 9H)

Reference Example 5004′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile

A solution of N-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazol-5-amine (2.2g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.30 mL) and ethyl2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (7.4 g) indiethylaniline (10 mL) was stirred at 180° C. for 2 hr. The mixture wasallowed to cool, ethyl acetate and water were added, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (4.0 g, 75%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.4 Hz, 3H), 1.64-1.92 (m,8H), 2.49-2.70 (m, 2H), 3.00-3.15 (m, 2H), 3.90-4.07 (m, 6H), 5.08-5.38(m, 1H), 6.19 (d, J=2.3 Hz, 1H), 7.19-7.79 (m, 8H)

Reference Example 5013′-fluoro-4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile(4.0 g) in tetrahydrofuran (40 mL) was added 3M hydrochloric acid (40mL), and the mixture was stirred at 70° C. for 2 hr. The mixture wasallowed to cool, and diluted with ethyl acetate, and the mixture wasneutralized with 8M aqueous sodium hydroxide solution. The mixture wasextracted with ethyl acetate, and the organic layer was washed withwater and saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was dissolved in ethanol (20mL)-tetrahydrofuran (20 mL), and sodium borohydride (0.28 g) was addedat 0° C. After stirring for 1 hr, ethyl acetate and saturated aqueousammonium chloride solution were added. The mixture was extracted withethyl acetate, and the organic layer was washed with water and saturatedbrine, dried over anhydrous magnesium sulfate, and concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound as a pale-yellow amorphous solid (3.3 g, 91%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.2 Hz, 3H), 1.42-1.90 (m,7H), 2.08-2.22 (m, 2H), 2.36-2.62 (m, 2H), 3.00-3.14 (m, 2H), 3.68-3.85(m, 1H), 4.02 (s, 2H), 4.55-5.04 (m, 1H), 5.99 (d, J=1.9 Hz, 1H),7.20-7.83 (m, 9H)

Reference Example 502 ethyl[(trans-4-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate

To a solution of3′-fluoro-4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(3.3 g) and rhodium acetate (dimer, 0.075 g) in methylene chloride (15mL) was added dropwise a solution of ethyl diazoacetate (3.1 mL) inmethylene chloride (5 mL), and the mixture was stirred for 3 hr. Ethylacetate and water were added to the reaction mixture, and the mixturewas extracted with ethyl acetate. The organic layer was washed withwater and then with saturated brine, dried over anhydrous magnesiumsulfate, and concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (2.1 g, 53%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.3 Hz, 3H), 1.21-1.92 (m,9H), 2.17-2.54 (m, 4H), 3.01-3.10 (m, 2H), 3.38-3.54 (m, 1H), 4.01 (s,2H), 4.13 (s, 2H), 4.23 (q, J=7.2 Hz, 2H), 4.53-4.96 (m, 1H), 5.97 (d,J=2.1 Hz, 1H), 7.20-7.78 (m, 9H)

Reference Example 5033′-fluoro-4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution ofethyl[(trans-4-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate(0.40 g) in tetrahydrofuran (4 mL) was added dropwise methylmagnesiumbromide (1 M tetrahydrofuran solution, 0.71 mL) at 0° C., and themixture was stirred for 30 min. To the reaction mixture were added ethylacetate and then saturated aqueous ammonium chloride solution, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (0.26 g, 88%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.3 Hz, 3H), 1.21 (s, 6H),1.36-1.54 (m, 2H), 1.62-1.92 (m, 4H), 2.15-2.26 (m, 2H), 2.34-2.54 (m,2H), 3.00-3.10 (m, 2H), 3.27-3.46 (m, 3H), 4.02 (s, 2H), 4.52-4.98 (m,1H), 5.98 (d, J=2.1 Hz, 1H), 7.19-7.81 (m, 8H)

Reference Example 5042-[(trans-4-{7-butyl-6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxopyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide

To a solution of ethyl[(trans-4-{7-butyl-6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxopyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate(1.68 g) in tetrahydrofuran (15 mL) was added 1 M aqueous sodiumhydroxide solution (15 mL), and the mixture was stirred at 60° C. for 2hr. The mixture was allowed to cool, and neutralized with 1 Mhydrochloric acid, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and then with saturated brine, driedover anhydrous magnesium sulfate, and concentrated. The residue wasdissolved in acetonitrile (30 mL), methoxymethylamine hydrochloride(0.87 g), 4-dimethylaminopyridine (0.11 g), diisopropylethylamine (2.6mL), 1-hydroxybenzotriazole (0.52 g) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.1 g) wereadded, and the mixture was stirred for 3 hr. Ethyl acetate and waterwere added to the reaction mixture, and the mixture was extracted withethyl acetate. The organic layer was washed with water and then withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (1.23 g, 71%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.94 (t, J=7.4 Hz, 3H), 1.37-1.92 (m,10H), 2.21-2.53 (m, 4H), 3.02-3.11 (m, 2H), 3.20 (s, 3H), 3.42-3.58 (m,1H), 3.70 (s, 3H), 4.00 (s, 2H), 4.33 (s, 2H), 4.80 (br. s., 1H), 5.98(d, J=2.3 Hz, 1H), 7.33-7.78 (m, 9H)

Reference Example 5054′-({7-butyl-4-[trans-4-(2-hydroxypropoxy)cyclohexyl]-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of2-[(trans-4-{7-butyl-6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxopyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide(0.30 g) in tetrahydrofuran (3 mL) was added dropwise methylmagnesiumbromide (1 M tetrahydrofuran solution, 0.74 mL) at 0° C., and themixture was stirred for 1 hr. Ethyl acetate and then saturated aqueousammonium chloride solution were added. The mixture was extracted withethyl acetate, and the organic layer was washed with saturated brine,dried over anhydrous magnesium sulfate, and concentrated. The residuewas dissolved in ethanol (6 mL), and sodium borohydride (0.020 g) wasadded at 0° C. After stirring at 0° C. for 30 min, ethyl acetate andthen saturated aqueous ammonium chloride solution were added. Themixture was extracted with ethyl acetate, and the organic layer waswashed with saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (0.27 g, 98%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.94 (t, J=7.4 Hz, 3H), 1.15 (d, J=6.4Hz, 3H), 1.36-1.54 (m, 4H), 1.61-1.93 (m, 4H), 2.14-2.56 (m, 5H),3.00-3.57 (m, 5H), 3.87-4.05 (m, 3H), 4.75 (br. s., 1H), 5.98 (d, J=1.9Hz, 1H), 7.32-7.78 (m, 9H)

Reference Example 5062-[(trans-4-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide

To a solution of ethyl[(trans-4-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate(1.68 g) in tetrahydrofuran (15 mL) was added 1 M aqueous sodiumhydroxide solution (15 mL), and the mixture was stirred at 60° C. for 2hr. The mixture was allowed to cool, and neutralized with 1 Mhydrochloric acid, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and then with saturated brine, driedover anhydrous magnesium sulfate, and concentrated. The residue wasdissolved in acetonitrile (30 mL), methoxymethylamine hydrochloride(0.87 g), 4-dimethylaminopyridine (0.11 g), diisopropylethylamine (2.6mL), 1-hydroxybenzotriazole (0.52 g) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.1 g) wereadded, and the mixture was stirred for 3 hr. Ethyl acetate and waterwere added to the reaction mixture, and the mixture was extracted withethyl acetate. The organic layer was washed with water and then withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (1.49 g, 83%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.4 Hz, 3H), 1.41-1.92 (m,8H), 2.19-2.57 (m, 4H), 3.01-3.11 (m, 2H), 3.20 (s, 3H), 3.41-3.58 (m,1H), 3.70 (s, 3H), 4.02 (s, 2H), 4.33 (s, 2H), 4.79 (br. s., 1H), 5.98(d, J=2.3 Hz, 1H), 7.16-7.81 (m, 8H)

Reference Example 5073′-fluoro-4′-({4-[trans-4-(2-hydroxypropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of2-[(trans-4-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide(0.30 g) in tetrahydrofuran (3 mL) was added dropwise methylmagnesiumbromide (1 M tetrahydrofuran solution, 0.73 mL) at 0° C., and themixture was stirred for 1 hr. Ethyl acetate and then saturated aqueousammonium chloride solution were added. The mixture was extracted withethyl acetate, and the organic layer was washed with saturated brine,dried over anhydrous magnesium sulfate, and concentrated. The residuewas dissolved in ethanol (6 mL), and sodium borohydride (0.020 g) wasadded at 0° C. After stirring at 0° C. for 30 min, ethyl acetate andthen saturated aqueous ammonium chloride solution were added. Themixture was extracted with ethyl acetate, and the organic layer waswashed with saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (0.28 g, 99%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.4 Hz, 3H), 1.03 (d, J=6.1 Hz,3H), 1.25-1.74 (m, 6H), 2.02-2.46 (m, 4H), 2.90-3.00 (m, 2H), 3.17-3.45(m, 3H), 3.62-3.76 (m, 1H), 3.92 (s, 2H), 4.46-4.85 (m, 2H), 6.43 (d,J=2.3 Hz, 1H), 6.95-7.89 (m, 8H), 12.44 (s, 1H)

Reference Example 5084′-({4-[trans-4-(2-hydroxypropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(optically active form, retention time: short)

A racemate of4′-({4-[trans-4-(2-hydroxypropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(1.0 g) was optically resolved by chiral HPLC to give an opticallyactive form (retention time: short) as a pale-yellow amorphous solid(0.42 g, 79%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.4 Hz, 3H), 1.15 (d, J=6.4Hz, 3H), 1.34-1.54 (m, 2H), 1.64-1.91 (m, 4H), 2.13-2.28 (m, 2H),2.33-2.55 (m, 3H), 3.06 (dd, J=10.4, 5.5 Hz, 2H), 3.20-3.29 (m, 1H),3.32-3.45 (m, 1H), 3.51 (dd, J=9.1, 3.0 Hz, 1H), 3.87-4.04 (m, 3H), 4.76(br. s., 1H), 5.98 (d, J=1.9 Hz, 1H), 7.33-7.77 (m, 9H)

HPLC (CHIRALPAK AD-H, 25% MeOH, 2.35 mL/min), 20.9 min, 98.8% ee

Reference Example 5094′-({4-[trans-4-(2-hydroxypropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(optically active form, retention time: long)

A racemate of4′-({4-[trans-4-(2-hydroxypropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(1.0 g) was optically resolved by chiral HPLC to give an opticallyactive form (retention time: long) as a pale-yellow amorphous solid(0.43 g, 82%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.4 Hz, 3H), 1.15 (d, J=6.4Hz, 3H), 1.34-1.54 (m, 2H), 1.64-1.91 (m, 4H), 2.13-2.28 (m, 2H),2.33-2.55 (m, 3H), 3.06 (dd, J=10.4, 5.5 Hz, 2H), 3.20-3.29 (m, 1H),3.32-3.45 (m, 1H), 3.51 (dd, J=9.1, 3.0 Hz, 1H), 3.87-4.04 (m, 3H), 4.76(br. s., 1H), 5.98 (d, J=1.9 Hz, 1H), 7.33-7.77 (m, 9H)

HPLC (CHIRALPAK AD-H, 25% MeOH, 2.35 mL/min), 23.4 min, 99.3% ee

Reference Example 5104′-{[4-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(1.68 g) and imidazole (0.74 g) in N,N-dimethylformamide (20 mL) wasadded tert-butyl(chloro)dimethylsilane (1.1 g), and the mixture wasstirred for 2 hr. To the reaction mixture were added ethyl acetate andsaturated aqueous sodium hydrogen carbonate solution, and the mixturewas extracted with ethyl acetate. The organic layer was washed withwater and then with saturated brine, dried over anhydrous magnesiumsulfate, and concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (1.89 g, 90%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.07 (s, 6H), 0.89 (s, 9H), 1.05 (t,J=7.4 Hz, 3H), 1.37-1.54 (m, 2H), 1.63-1.84 (m, 4H), 1.94-2.04 (m, 2H),2.36-2.57 (m, 2H), 3.00-3.10 (m, 2H), 3.62-3.76 (m, 1H), 4.01 (s, 2H),4.63 (br. s., 1H), 5.98 (d, J=1.9 Hz, 1H), 7.31-7.84 (m, 9H)

Reference Example 5114′-{[4-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-3-fluoro-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-{[4-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(1.76 g) in acetonitrile (15 mL) was added1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (1.1 g), and the mixture was stirred at 80° C.for 3 hr. To the reaction mixture were added ethyl acetate and saturatedaqueous sodium hydrogen carbonate solution, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand then with saturated brine, dried over anhydrous magnesium sulfate,and concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (0.24 g, 13%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.06 (s, 6H), 0.86 (s, 9H), 0.93 (t, J=7.3Hz, 3H), 1.28-1.97 (m, 8H), 2.09-2.38 (m, 2H), 2.86-3.05 (m, 2H),3.56-3.71 (m, 1H), 3.96 (s, 2H), 4.71 (br. s., 1H), 7.34-8.09 (m, 9H)

Reference Example 512 ethyl[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-3-fluoro-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate

To a solution of4′-{[4-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-3-fluoro-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.24 g) in tetrahydrofuran (2 mL) was added tetrabutylammonium fluoride(1 mL), and the mixture was stirred at 70° C. for 2 hr. Ethyl acetateand saturated aqueous ammonium chloride solution were added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and then with saturated brine, driedover anhydrous magnesium sulfate, and concentrated. The residue wasdissolved in toluene (2 mL), rhodium acetate (dimer, 0.016 g) was added,ethyl diazoacetate (0.19 mL) was added dropwise at 100° C., and themixture was stirred for 3 hr. Ethyl acetate and water were added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and then with saturated brine, driedover anhydrous magnesium sulfate, and concentrated. The residue waspurified by silica gel column chromatography to give the title compoundas a pale-yellow amorphous solid (0.087 g, 42%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H), 1.20 (t, J=7.2 Hz,3H), 1.26-2.23 (m, 10H), 2.90-3.00 (m, 2H), 3.33-3.45 (m, 1H), 3.96 (s,2H), 4.06-4.17 (m, 4H), 4.75 (br. s., 1H), 7.34-8.11 (m, 9H)

Reference Example 5131-benzyl-N-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-pyrazol-5-amine

To a solution of 1-benzyl-1H-pyrazol-5-amine (6.3 g) in acetic acid (70mL) was added 4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexanone (10 g) andthe mixture was stirred for 30 min. After stirring, sodiumtriacetoxyborohydride (12.0 g) was added, and the mixture was stirredfor 18 hr. Acetic acid was evaporated and ethyl acetate and water wereadded to the residue. The mixture was neutralized with sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organiclayer was washed with water and saturated brine, dried over anhydrousmagnesium sulfate, and concentrated. The residue was purified by silicagel column chromatography to give the title compound as a pale-yellowamorphous solid (1.27 g, 9%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.01-0.06 (m, 6H), 0.83-0.91 (m, 9H),1.14-1.96 (m, 8H), 2.87-3.11 (m, 1H), 3.52-3.91 (m, 1H), 5.05-5.41 (m,4H), 7.02-7.33 (m, 6H)

Reference Example 514N-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-pyrazol-5-amine

To a suspension of1-benzyl-N-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-pyrazol-5-amine(1.3 g) and palladium hydroxide (10 wt %, 1.27 g) in ethanol (6mL)-acetic acid (0.6 mL) was added ammonium formate (0.62 g) by smallportions at 80° C. After stirring at 80° C. for 2 hr, the mixture wasallowed to cool, ethyl acetate was added, and the insoluble material wasfiltered off. Saturated aqueous sodium hydrogen carbonate was added tothe filtrate, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine, dried overanhydrous magnesium sulfate, and concentrated. The residue was purifiedby silica gel column chromatography to give the title compound as apale-yellow amorphous solid (0.68 g, 69%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.00-0.07 (m, 6H), 0.81-0.91 (m, 9H),1.03-2.01 (m, 8H), 3.00-3.24 (m, 1H), 3.53-3.92 (m, 1H), 4.68-5.14 (m,1H), 5.38 (s, 1H), 7.26 (br. s., 1H), 11.34 (br. s., 1H)

Reference Example 5152-(5-{[7-butyl-4-(trans-4-hydroxycyclohexyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}pyridin-2-yl)benzonitrile

A solution ofN-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-pyrazol-5-amine(0.67 g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.067 mL) and methyl2-{[6-(2-cyanophenyl)pyridin-3-yl]methyl}-3-oxoheptanoate (0.8 g) indiethylaniline (5 mL) was stirred at 180° C. for 5 hr. The mixture wasallowed to cool, ethyl acetate and water were added, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was crudely purified by silica gel columnchromatography. This was dissolved in tetrahydrofuran (4 mL).Tetrabutylammonium fluoride (2.5 mL) was added, and the mixture wasstirred at 70° C. for 2 hr. The mixture was allowed to cool, ethylacetate and saturated aqueous ammonium chloride solution were added, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with water and saturated brine, dried over anhydrous magnesiumsulfate, and concentrated. This was dissolved in acetonitrile (6 mL),1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (1.0 g) wasadded, and the mixture was stirred for 3 hr. Ethyl acetate, water andsodium thiosulfate were added to the reaction mixture, and the mixturewas stirred for 30 min. After stirring, the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate, and the solvent was evaporated.The residue was dissolved in ethanol (3 mL)-tetrahydrofuran (3 mL), andsodium borohydride (0.045 g) was added at 0° C. After stirring at 0° C.for 2 hr, ethyl acetate and then saturated aqueous ammonium chloridesolution were added. The mixture was extracted with ethyl acetate, andthe organic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate, and concentrated. The residue was purified by silicagel column chromatography to give the title compound as a pale-yellowamorphous solid (0.48 g, 44%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.78-0.89 (m, 3H), 1.26-1.70 (m, 8H),1.85-1.97 (m, 2H), 2.25-2.46 (m, 2H), 2.98-3.10 (m, 2H), 3.46-3.65 (m,1H), 3.99 (s, 2H), 4.51-4.81 (m, 2H), 6.42 (d, J=2.3 Hz, 1H), 7.56-7.99(m, 7H), 8.65 (d, J=0.9 Hz, 1H)

Reference Example 516 ethyl({trans-4-[7-butyl-6-{[6-(2-cyanophenyl)pyridin-3-yl]methyl}-5-oxopyrazolo[1,5-a]pyrimidin-4(5H)-yl]cyclohexyl}oxy)acetate

To a solution of2-(5-{[7-butyl-4-(trans-4-hydroxycyclohexyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}pyridin-2-yl)benzonitrile(0.48 g) and rhodium acetate (dimer, 0.044 g) in toluene (5 mL) wasadded dropwise ethyl diazoacetate (0.52 mL), and the mixture was stirredfor 5 hr. Ethyl acetate and water were added to the reaction mixture,and the mixture was extracted with ethyl acetate. The organic layer waswashed with water and then with saturated brine, dried over anhydrousmagnesium sulfate, and concentrated. The residue was purified by silicagel column chromatography to give the title compound as a pale-yellowamorphous solid (0.26 g, 47%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.80-0.87 (m, 3H), 1.21 (t, J=7.2 Hz, 3H),1.30-1.73 (m, 8H), 2.03-2.17 (m, 2H), 2.29-2.47 (m, 2H), 2.99-3.08 (m,2H), 3.41-3.54 (m, 1H), 3.98 (s, 2H), 4.08-4.17 (m, 4H), 4.68 (br. s.,1H), 6.43 (d, J=2.3 Hz, 1H), 7.58-7.98 (m, 7H), 8.65 (s, 1H)

Reference Example 5172-[5-({7-butyl-4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)pyridin-2-yl]benzonitrile

To a solution of ethyl({trans-4-[7-butyl-6-{[6-(2-cyanophenyl)pyridin-3-yl]methyl}-5-oxopyrazolo[1,5-a]pyrimidin-4(5H)-yl]cyclohexyl}oxy)acetate(0.26 g) in tetrahydrofuran (3 mL) was added dropwise methylmagnesiumbromide (1 M tetrahydrofuran solution, 1.4 mL) at 0° C., and the mixturewas stirred for 3 hr. To the reaction mixture were added ethyl acetateand then saturated aqueous ammonium chloride solution, and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (0.16 g, 63%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (t, J=7.2 Hz, 3H), 1.07 (s, 6H),1.30-1.74 (m, 8H), 2.04-2.46 (m, 4H), 3.00-3.08 (m, 2H), 3.19 (s, 2H),3.35-3.45 (m, 1H), 3.99 (s, 2H), 4.24 (s, 1H), 4.66 (br. s., 1H), 6.43(d, J=1.9 Hz, 1H), 7.57-7.98 (m, 7H), 8.65 (s, 1H)

Reference Example 5184′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}-2′-fluorobiphenyl-2-carbonitrile

A solution of N-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazol-5-amine (2.2g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.30 mL) and ethyl2-[(2′-cyano-2-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (6.4 g) indiethylaniline (10 mL) was stirred at 180° C. for 2 hr. The mixture wasallowed to cool, ethyl acetate and water were added, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (4.3 g, 82%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.87-1.01 (m, 3H), 1.46-1.84 (m, 8H),2.53-2.63 (m, 2H), 2.94-3.04 (m, 2H), 3.84-4.02 (m, 6H), 4.82 (br. s.,1H), 6.24 (s, 1H), 7.18-8.01 (m, 8H)

Reference Example 5192′-fluoro-4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}-2′-fluorobiphenyl-2-carbonitrile(4.3 g) in tetrahydrofuran (40 mL) was added 3M hydrochloric acid (40mL), and the mixture was stirred at 70° C. for 2 hr. The mixture wasallowed to cool, and diluted with ethyl acetate, and the mixture wasneutralized with 8M aqueous sodium hydroxide solution. The mixture wasextracted with ethyl acetate, and the organic layer was washed withwater and saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was dissolved in ethanol (15mL)-tetrahydrofuran (15 mL). Thereto was added sodium borohydride (0.25g) at 0° C. After stirring for 2 hr, ethyl acetate and saturated aqueousammonium chloride solution were added. The mixture was extracted withethyl acetate, and the organic layer was washed with water and saturatedbrine, dried over anhydrous magnesium sulfate, and concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound as a pale-yellow amorphous solid (3.0 g, 91%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.3 Hz, 3H), 1.25-1.98 (m, 8H),2.29-2.46 (m, 2H), 2.89-3.07 (m, 2H), 3.48-3.65 (m, 1H), 3.99 (s, 2H),4.50-4.84 (m, 2H), 6.42 (d, J=2.3 Hz, 1H), 7.18-8.01 (m, 8H)

Reference Example 520 ethyl[(trans-4-{6-[(2′-cyano-2-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate

To a solution of2′-fluoro-4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.48 g) and rhodium acetate (dimer, 0.044 g) in toluene (5 mL) wasadded dropwise ethyl diazoacetate (0.52 mL) at 100° C., and the mixturewas stirred for 5 hr. Ethyl acetate and water were added to the reactionmixture, and the mixture was extracted with ethyl acetate. The organiclayer was washed with water and then with saturated brine, dried overanhydrous magnesium sulfate, and concentrated. The residue was purifiedby silica gel column chromatography to give the title compound as apale-yellow amorphous solid (0.33 g, 58%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.3 Hz, 3H), 1.21 (t, J=7.2 Hz,3H), 1.30-1.73 (m, 6H), 2.03-2.46 (m, 4H), 2.94-3.02 (m, 2H), 3.40-3.56(m, 1H), 3.99 (s, 2H), 4.07-4.17 (m, 4H), 4.66 (br. s., 1H), 6.43 (d,J=2.3 Hz, 1H), 7.17-7.99 (m, 9H)

Reference Example 5212′-fluoro-4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of ethyl[(trans-4-{6-[(2′-cyano-2-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate(0.33 g) in tetrahydrofuran (3 mL) was added dropwise methylmagnesiumbromide (1 M tetrahydrofuran solution, 1.74 mL) at 0° C., and themixture was stirred for 3 hr. To the reaction mixture were added ethylacetate and then saturated aqueous ammonium chloride solution, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (0.23 g, 72%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.4 Hz, 3H), 1.07 (s, 6H),1.26-1.75 (m, 6H), 2.03-2.45 (m, 4H), 2.94-3.02 (m, 2H), 3.19 (s, 2H),3.35-3.46 (m, 1H), 3.99 (s, 2H), 4.25 (s, 1H), 4.68 (br. s., 1H), 6.43(d, J=1.9 Hz, 1H), 7.17-7.99 (m, 8H)

Reference Example 5224′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}-2′-methylbiphenyl-2-carbonitrile

A solution of N-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazol-5-amine (0.59g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.080 mL) and ethyl2-[(2′-cyano-2-methylbiphenyl-4-yl)methyl]-3-oxohexanoate (1.5 g) indiethylaniline (3 mL) was stirred at 180° C. for 2 hr. The mixture wasallowed to cool, ethyl acetate and water were added, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (1.0 g, 74%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.3 Hz, 3H), 1.46-1.83 (m, 8H),2.08 (s, 3H), 2.54-2.65 (m, 2H), 2.92-3.05 (m, 2H), 3.84-3.97 (m, 6H),4.81 (br. s., 1H), 6.23 (s, 1H), 7.05-7.98 (m, 8H)

Reference Example 5234′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}-2′-methylbiphenyl-2-carbonitrile

To a solution of4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}-2′-methylbiphenyl-2-carbonitrile(1.0 g) in tetrahydrofuran (10 mL) was added 3M hydrochloric acid (10mL), and the mixture was stirred at 60° C. for 12 hr. The mixture wasallowed to cool, and diluted with ethyl acetate, and the mixture wasneutralized with 1 M aqueous sodium hydroxide solution. The mixture wasextracted with ethyl acetate, and the organic layer was washed withwater and saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was dissolved in ethanol (5mL)-tetrahydrofuran (5 mL). Sodium borohydride (0.074 g) was addedthereto at 0° C. After stirring for 2 hr, ethyl acetate and saturatedaqueous ammonium chloride solution were added. The mixture was extractedwith ethyl acetate, and the organic layer was washed with water andsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (0.88 g, 94%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.3 Hz, 3H), 1.26-1.69 (m, 6H),1.86-1.98 (m, 2H), 2.08 (s, 3H), 2.28-2.46 (m, 2H), 2.92-3.02 (m, 2H),3.51-3.58 (m, 1H), 3.93 (s, 2H), 4.55-4.81 (m, 2H), 6.41 (d, J=2.3 Hz,1H), 7.03-8.02 (m, 8H)

Reference Example 5244′-{1-[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]ethyl}biphenyl-2-carbonitrile

A solution of N-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazol-5-amine (0.59g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.080 mL) and ethyl2-[1-(2′-cyanobiphenyl-4-yl)ethyl]-3-oxohexanoate (0.5 g) indiethylaniline (3 mL) was stirred at 180° C. for 2 hr. The mixture wasallowed to cool, ethyl acetate and water were added, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (1.0 g, 74%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.4 Hz, 3H), 1.30-1.82 (m, 12H),2.38-2.48 (m, 2H), 2.88-3.11 (m, 2H), 3.83-3.98 (m, 4H), 4.47-4.99 (m,2H), 6.19 (d, J=1.5 Hz, 1H), 7.40-7.98 (m, 9H)

Reference Example 5254′-{1-[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]ethyl}biphenyl-2-carbonitrile

To a solution of4′-{1-[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]ethyl}biphenyl-2-carbonitrile(0.37 g) in tetrahydrofuran (4 mL) was added 3M hydrochloric acid (4mL), and the mixture was stirred at 60° C. for 3 hr. The mixture wasallowed to cool, and diluted with ethyl acetate, and the mixture wasneutralized with 1 M aqueous sodium hydroxide solution. The mixture wasextracted with ethyl acetate, and the organic layer was washed withwater and saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was dissolved in ethanol (3mL)-tetrahydrofuran (3 mL). Thereto was added sodium borohydride (0.026g) at 0° C. After stirring for 2 hr, ethyl acetate and saturated aqueousammonium chloride solution were added. The mixture was extracted withethyl acetate, and the organic layer was washed with water and saturatedbrine, dried over anhydrous magnesium sulfate, and concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound as a pale-yellow amorphous solid (0.33 g, 99%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91 (t, J=7.3 Hz, 3H), 1.23-1.96 (m, 11H),2.18-2.44 (m, 2H), 2.85-3.11 (m, 2H), 3.46-3.63 (m, 1H), 4.46-4.77 (m,3H), 6.37 (d, J=2.1 Hz, 1H), 7.38-8.01 (m, 9H)

Reference Example 5264′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}-2′-nitrobiphenyl-2-carbonitrile

A solution of N-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazol-5-amine (0.45g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.060 mL) and ethyl2-[(2′-cyano-2-nitrobiphenyl-4-yl)methyl]-3-oxohexanoate (1.6 g) indiethylaniline (2 mL) was stirred at 180° C. for 2 hr. The mixture wasallowed to cool, ethyl acetate and water were added, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (0.96 g, 87%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.96 (t, J=7.4 Hz, 3H), 1.48-1.85 (m, 8H),2.53-2.66 (m, 2H), 2.97-3.08 (m, 2H), 3.84-3.98 (m, 4H), 4.10 (s, 2H),4.79 (br. s., 1H), 6.25 (s, 1H), 7.41-8.14 (m, 8H)

Reference Example 5274′-{[7-butyl-4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}-2′-fluorobiphenyl-2-carbonitrile

A solution of N-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazol-5-amine (2.2g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.30 mL) and methyl2-[(2′-cyano-2-fluorobiphenyl-4-yl)methyl]-3-oxoheptanoate (6.4 g) indiethylaniline (10 mL) was stirred at 180° C. for 2 hr. The mixture wasallowed to cool, ethyl acetate and water were added, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (4.7 g, 87%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.73-0.93 (m, 3H), 1.28-1.85 (m, 10H),2.52-2.66 (m, 2H), 2.93-3.06 (m, 2H), 3.84-4.01 (m, 6H), 4.81 (br. s.,1H), 6.24 (s, 1H), 7.19-8.00 (m, 8H)

Reference Example 5284′-{[7-butyl-4-(trans-4-hydroxycyclohexyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}-2′-fluorobiphenyl-2-carbonitrile

To a solution of4′-{[7-butyl-4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}-2′-fluorobiphenyl-2-carbonitrile(4.7 g) in tetrahydrofuran (40 mL) was added 3M hydrochloric acid (40mL), and the mixture was stirred at 70° C. for 2 hr. The mixture wasallowed to cool, and diluted with ethyl acetate, and the mixture wasneutralized with 8M aqueous sodium hydroxide solution. The mixture wasextracted with ethyl acetate, and the organic layer was washed withwater and saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was dissolved in ethanol (20mL)-tetrahydrofuran (20 mL). Thereto was added sodium borohydride (0.26g) at 0° C. After stirring for 1 hr, ethyl acetate and saturated aqueousammonium chloride solution were added. The mixture was extracted withethyl acetate, and the organic layer was washed with water and saturatedbrine, dried over anhydrous magnesium sulfate, and concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound as a pale-yellow amorphous solid (3.3 g, 98%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.79-0.88 (m, 3H), 1.27-1.98 (m, 10H),2.27-2.46 (m, 2H), 2.94-3.05 (m, 2H), 3.49-3.65 (m, 1H), 3.99 (s, 2H),4.55-4.80 (m, 2H), 6.42 (d, J=2.3 Hz, 1H), 7.18-8.01 (m, 8H)

Reference Example 529 ethyl[(trans-4-{7-butyl-6-[(2′-cyano-2-fluorobiphenyl-4-yl)methyl]-5-oxopyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate

To a solution of4′-{[7-butyl-4-(trans-4-hydroxycyclohexyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}-2′-fluorobiphenyl-2-carbonitrile(1.0 g) and rhodium acetate (dimer, 0.044 g) in toluene (10 mL) wasadded dropwise ethyl diazoacetate (0.83 mL) at 100° C., and the mixturewas stirred for 5 hr. Ethyl acetate and water were added to the reactionmixture, and the mixture was extracted with ethyl acetate. The organiclayer was washed with water and then with saturated brine, dried overanhydrous magnesium sulfate, and concentrated. The residue was purifiedby silica gel column chromatography to give the title compound as apale-yellow amorphous solid (0.47 g, 42%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (t, J=7.2 Hz, 3H), 1.17-1.24 (m, 3H),1.28-2.47 (m, 12H), 2.94-3.05 (m, 2H), 3.39-3.58 (m, 1H), 3.94-4.16 (m,4H), 4.67 (br. s., 1H), 6.43 (d, J=2.1 Hz, 1H), 7.16-8.00 (m, 7H)

Reference Example 5304′-({7-butyl-4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)-2′-fluorobiphenyl-2-carbonitrile

To a solution of ethyl[(trans-4-{7-butyl-6-[(2′-cyano-2-fluorobiphenyl-4-yl)methyl]-5-oxopyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate(0.47 g) in tetrahydrofuran (4 mL) was added dropwise methylmagnesiumbromide (1 M tetrahydrofuran solution, 1.8 mL) at 0° C., and the mixturewas stirred for 2 hr. To the reaction mixture were added ethyl acetateand then saturated aqueous ammonium chloride solution, and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (0.32 g, 66%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (t, J=7.2 Hz, 3H), 1.07 (s, 6H),1.27-1.80 (m, 8H), 2.02-2.46 (m, 4H), 2.94-3.04 (m, 2H), 3.35-3.46 (m,1H), 3.99 (s, 2H), 4.25 (s, 1H), 4.68 (br. s., 1H), 6.43 (d, J=2.1 Hz,1H), 7.15-7.99 (m, 8H)

Reference Example 5311-benzyl-N-[4-(1-methylethoxy)phenyl]-1H-pyrazol-5-amine

A suspension of 1-benzyl-1H-pyrazol-5-amine (1.7 g),4-isopropylphenylboric acid (2.0 g), copper acetate (1.8 g), pyridine(4.0 mL) and molecular sieves 4A (4 g) in tetrahydrofuran (50 mL) wasstirred for 15 hr. The reaction mixture was diluted with ethyl acetate,the insoluble material was filtered off through celite, and the filtratewas concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (0.80 g, 26%).

¹H NMR (300 MHz, DMSO-d₆) δ 1.21 (d, J=6.1 Hz, 6H), 4.42 (spt, J=6.1 Hz,1H), 5.23 (s, 2H), 5.90 (d, J=1.9 Hz, 1H), 6.73-6.86 (m, 4H), 7.05-7.41(m, 6H), 7.75 (s, 1H)

Reference Example 532 N-[4-(1-methylethoxy)phenyl]-1H-pyrazol-5-amine

To a suspension of1-benzyl-N-[4-(1-methylethoxy)phenyl]-1H-pyrazol-5-amine (0.80 g) andpalladium hydroxide (10 wt %, 0.80 g) in ethanol (4.5 mL)-acetic acid(0.5 mL) was added ammonium formate (0.49 g) at 80° C. After stirring at80° C. for 2 hr, the mixture was allowed to cool, ethyl acetate wasadded, and the insoluble material was filtered off. Saturated aqueoussodium hydrogen carbonate solution was added to the filtrate, and themixture was extracted with ethyl acetate. The organic layer was washedwith water and saturated brine, dried over anhydrous magnesium sulfate,and concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (0.37 g, 66%).

¹H NMR (300 MHz, DMSO-d₆) δ 1.21 (d, J=6.0 Hz, 6H), 4.41 (spt, J=6.0 Hz,1H), 5.74 (d, J=2.1 Hz, 1H), 6.70-6.81 (m, 2H), 7.24 (d, J=8.5 Hz, 2H),7.50 (s, 1H), 8.06 (s, 1H), 11.83 (br. s., 1H)

Reference Example 5334′-({4-[4-(1-methylethoxy)phenyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

N-[4-(1-Methylethoxy)phenyl]-1H-pyrazol-5-amine (0.37 g) and a solutionof 1,8-diazabicyclo[5.4.0]undec-7-ene (0.051 mL) and ethyl2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (1.2 g) indiethylaniline (5 mL) were stirred at 180° C. for 1 hr. The mixture wasallowed to cool, ethyl acetate and water were added, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (0.76 g, 89%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.98 (t, J=7.3 Hz, 3H), 1.31 (d, J=6.0 Hz,6H), 1.55-1.72 (m, 2H), 2.99-3.10 (m, 2H), 4.02 (s, 2H), 4.69 (spt,J=6.1 Hz, 1H), 5.45 (d, J=2.1 Hz, 1H), 7.01-7.98 (m, 13H)

Reference Example 534 methyl 2′-cyano-3-methoxybiphenyl-4-carboxylate

A suspension of methyl 4-bromo-2-methoxybenzoate (4.9 g),(2-cyanophenyl)boronic acid (5.9 g), Pd(dppf)₂Cl₂ (0.49 g) and 2Maqueous cesium carbonate solution (20 mL) in tetrahydrofuran (60 mL) wasstirred under an argon atmosphere at 70° C. for 3 hr. The mixture wasallowed to cool, ethyl acetate and water were added, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (1.9 g, 35%).

¹H NMR (300 MHz, DMSO-d₆) δ 3.82 (s, 3H), 3.90 (s, 3H), 7.18-8.04 (m,7H)

Reference Example 535 ethyl2-[(2′-cyano-3-methoxybiphenyl-4-yl)methyl]-3-oxohexanoate

To a solution of methyl 2′-cyano-3-methoxybiphenyl-4-carboxylate (1.86g) in tetrahydrofuran (40 mL) was added lithium borohydride (0.67 g) at0° C., and the mixture was stirred at room temperature for 12 hr. To thereaction mixture were added ethyl acetate and saturated aqueous ammoniumchloride solution, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine, dried overanhydrous magnesium sulfate, and concentrated. The residue was dissolvedin toluene (30 mL), phosphorus tribromide (0.33 mL) was added, and themixture was stirred for 3 hr. Ethyl acetate and water were added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine, dried overanhydrous magnesium sulfate, and concentrated. This was dissolved intetrahydrofuran (10 mL), the mixture was added dropwise to a solution ofethyl 3-oxohexanoate (1.7 g) and 60% sodium hydride (0.28 g) intetrahydrofuran (15 mL) at 0° C., and the mixture was stirred at roomtemperature for 15 hr. To the reaction mixture were added ethyl acetateand saturated aqueous ammonium chloride solution, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (1.8 g, 89%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.79 (t, J=7.4 Hz, 3H), 1.11 (t, J=7.2 Hz,3H), 1.39-1.52 (m, 2H), 2.37-2.47 (m, 2H), 2.97-3.15 (m, 2H), 3.87 (s,3H), 3.97-4.10 (m, 3H), 6.96-8.04 (m, 7H)

Reference Example 5364′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-methoxybiphenyl-2-carbonitrile

A solution of N-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazol-5-amine (0.53g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.071 mL) and ethyl2-[(2′-cyano-3-methoxybiphenyl-4-yl)methyl]-3-oxohexanoate (1.81 g) indiethylaniline (3 mL) was stirred at 180° C. for 2 hr. The mixture wasallowed to cool, ethyl acetate and water were added, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (1.1 g, 83%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.2 Hz, 3H), 1.46-1.86 (m, 8H),2.55-2.68 (m, 2H), 2.87-2.97 (m, 2H), 3.84-3.98 (m, 9H), 4.80 (br. s.,1H), 6.24 (s, 1H), 6.96-8.00 (m, 8H)

Reference Example 5374′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-methoxybiphenyl-2-carbonitrile

To a solution of4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-methoxybiphenyl-2-carbonitrile(1.1 g) in tetrahydrofuran (10 mL) was added 3M hydrochloric acid (10mL), and the mixture was stirred at 60° C. for 5 hr. The mixture wasallowed to cool, and diluted with ethyl acetate, and the mixture wasneutralized with 8M aqueous sodium hydroxide solution. The mixture wasextracted with ethyl acetate, and the organic layer was washed withwater and saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was dissolved in ethanol (10mL)-tetrahydrofuran (10 mL). Thereto was added sodium borohydride (0.075g) at 0° C. After stirring for 2 hr, ethyl acetate and saturated aqueousammonium chloride solution were added. The mixture was extracted withethyl acetate, and the organic layer was washed with water and saturatedbrine, dried over anhydrous magnesium sulfate, and concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound as a pale-yellow amorphous solid (0.93 g, 95%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H), 1.27-1.68 (m, 6H),1.87-1.97 (m, 2H), 2.25-2.47 (m, 2H), 2.85-2.97 (m, 2H), 3.48-3.63 (m,1H), 3.87 (s, 2H), 3.92 (s, 3H), 4.49-4.84 (m, 2H), 6.41 (d, J=2.1 Hz,1H), 6.89-8.07 (m, 8H)

Reference Example 538 ethyl[(trans-4-{6-[(2′-cyano-3-methoxybiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate

To a solution of4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-methoxybiphenyl-2-carbonitrile(0.93 g) and rhodium acetate (dimer, 0.020 g) in methylene chloride (10mL) was added dropwise ethyl diazoacetate (0.86 mL), and the mixture wasstirred for 3 hr. Ethyl acetate and water were added to the reactionmixture, and the mixture was extracted with ethyl acetate. The organiclayer was washed with water and then with saturated brine, dried overanhydrous magnesium sulfate, and concentrated. The residue was purifiedby silica gel column chromatography to give the title compound as apale-yellow amorphous solid (0.52 g, 47%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H), 1.17-1.25 (m, 3H),1.29-1.73 (m, 6H), 2.04-2.16 (m, 2H), 2.30-2.46 (m, 2H), 2.86-2.95 (m,2H), 3.40-3.54 (m, 1H), 3.86 (s, 2H), 3.92 (s, 3H), 4.07-4.18 (m, 4H),4.64 (br. s., 1H), 6.42 (d, J=2.3 Hz, 1H), 6.93-8.07 (m, 8H)

Reference Example 5394′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)-3′-methoxybiphenyl-2-carbonitrile

To a solution of ethyl[(trans-4-{6-[(2′-cyano-3-methoxybiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate(0.51 g) in tetrahydrofuran (5 mL) was added dropwise methylmagnesiumbromide (1 M tetrahydrofuran solution, 3.5 mL) at 0° C., and the mixturewas stirred for 3 hr. To the reaction mixture were added ethyl acetateand then saturated aqueous ammonium chloride solution, and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (0.44 g, 87%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H), 1.07 (s, 6 H),1.22-1.77 (m, 6H), 2.02-2.16 (m, 2H), 2.30-2.46 (m, 2H), 2.83-2.97 (m,2H), 3.19 (s, 2H), 3.34-3.45 (m, 1H), 3.87 (s, 2H), 3.92 (s, 3H), 4.24(s, 1H), 4.66 (br. s., 1H), 6.42 (d, J=2.1 Hz, 1H), 6.99-7.97 (m, 8H)

Reference Example 540 ethyl 2′-cyano-2-methoxybiphenyl-4-carboxylate

A suspension of ethyl3-methoxy-4-{[(trifluoromethyl)sulfonyl]oxy}benzoate (7.0 g),(2-cyanophenyl)boronic acid (5.9 g), Pd(dppf)₂Cl₂ (0.50 g) and 2Maqueous cesium carbonate solution (20 mL) in tetrahydrofuran (60 mL) wasstirred under an argon atmosphere at 70° C. for 3 hr. The mixture wasallowed to cool, ethyl acetate and water were added, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (0.28 g, 5%).

¹H NMR (300 MHz, DMSO-d₆) δ 1.35 (t, J=7.0 Hz, 3H), 3.84 (s, 3H), 4.37(q, J=7.2 Hz, 2H), 7.40-7.97 (m, 7H) Reference Example 541 ethyl2-[(2′-cyano-2-methoxybiphenyl-4-yl)methyl]-3-oxohexanoate

To a solution of ethyl 2′-cyano-2-methoxybiphenyl-4-carboxylate (0.28 g)in tetrahydrofuran (10 mL) was added lithium borohydride (0.22 g), andthe mixture was stirred at room temperature for 15 hr. To the reactionmixture were added ethyl acetate and saturated aqueous ammonium chloridesolution, and the mixture was extracted with ethyl acetate. The organiclayer was washed with water and saturated brine, dried over anhydrousmagnesium sulfate, and concentrated. The residue was dissolved intoluene (5 mL), phosphorus tribromide (0.050 mL) was added, and themixture was stirred for 1 hr. Ethyl acetate and water were added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine, dried overanhydrous magnesium sulfate, and concentrated. This was dissolved intetrahydrofuran (2 mL), the mixture was added dropwise to a solution ofethyl 3-oxohexanoate (0.25 g) and 60% sodium hydride (0.047 g) intetrahydrofuran (2 mL) at 0° C., and the mixture was stirred at roomtemperature for 15 hr. To the reaction mixture were added ethyl acetateand saturated aqueous ammonium chloride solution, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (0.26 g, 85%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.79 (t, J=7.4 Hz, 3H), 1.12 (t, J=7.2 Hz,3H), 1.38-1.53 (m, 2H), 2.38-2.62 (m, 2H), 3.01-3.19 (m, 2H), 3.75 (s,3H), 3.98-4.19 (m, 3H), 6.85-7.88 (m, 7H)

Reference Example 5424′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}-2′-methoxybiphenyl-2-carbonitrile

A solution of N-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazol-5-amine (0.30g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.017 mL) and ethyl2-[(2′-cyano-2-methoxybiphenyl-4-yl)methyl]-3-oxohexanoate (0.26 g) indiethylaniline (2 mL) was stirred at 180° C. for 2 hr. The mixture wasallowed to cool, ethyl acetate and water were added, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (0.25 g, 70%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91-0.99 (m, 3H), 1.48-1.83 (m, 8H),2.53-2.67 (m, 2H), 2.95-3.05 (m, 2H), 3.73 (s, 3H), 3.85-4.00 (m, 6H),4.80 (br. s., 1H), 6.24 (d, J=1.5 Hz, 1H), 6.84-7.90 (m, 8H)

Reference Example 543 ethyl[(trans-4-{6-[(2′-cyano-2-methoxybiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate

To a solution of4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}-2′-methoxybiphenyl-2-carbonitrile(0.25 g) in tetrahydrofuran (3 mL) was added 3M hydrochloric acid (3mL), and the mixture was stirred at 60° C. for 12 hr. The mixture wasallowed to cool, and diluted with ethyl acetate, and the mixture wasneutralized with 1 M aqueous sodium hydroxide solution. The mixture wasextracted with ethyl acetate, and the organic layer was washed withwater and saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was dissolved in ethanol (3mL)-tetrahydrofuran (3 mL). Thereto was added sodium borohydride (0.019g) at 0° C. After stirring for 1 hr, ethyl acetate and saturated aqueousammonium chloride solution were added. The mixture was extracted withethyl acetate, and the organic layer was washed with water and saturatedbrine, dried over anhydrous magnesium sulfate, and concentrated. Theresidue was dissolved in methylene chloride (2 mL), rhodium acetate(dimer, 0.020 g) and then ethyl diazoacetate (0.86 mL) were addeddropwise, and the mixture was stirred for 3 hr. Ethyl acetate and waterwere added to the reaction mixture, and the mixture was extracted withethyl acetate. The organic layer was washed with water and then withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (0.13 g, 53%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.2 Hz, 3H), 1.18-1.25 (m, 3H),1.29-1.80 (m, 6H), 2.03-2.45 (m, 4H), 2.93-3.04 (m, 2H), 3.40-3.55 (m,1H), 3.73 (s, 3H), 3.97 (s, 2H), 4.08-4.19 (m, 5H), 4.63 (br. s., 1H),6.42 (d, J=2.3 Hz, 1H), 6.81-7.91 (m, 8H)

Reference Example 5444′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)-2′-methoxybiphenyl-2-carbonitrile

To a solution of ethyl[(trans-4-{6-[(2′-cyano-2-methoxybiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate(0.13 g) in tetrahydrofuran (1.5 mL) was added dropwise methylmagnesiumbromide (1 M tetrahydrofuran solution, 0.88 mL) at 0° C., and themixture was stirred for 3 hr. To the reaction mixture were added ethylacetate and then saturated aqueous ammonium chloride solution, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (0.085 g, 68%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.2 Hz, 3H), 1.07 (s, 6H),1.27-1.77 (m, 6H), 2.03-2.15 (m, 2H), 2.31-2.47 (m, 2H), 2.94-3.04 (m,2H), 3.20 (s, 2H), 3.34-3.46 (m, 1H), 3.73 (s, 3H), 3.97 (s, 2H), 4.22(br. s., 1H), 4.65 (br. s., 1H), 6.42 (d, J=2.3 Hz, 1H), 6.80-7.93 (m,8H)

Reference Example 5451-benzyl-N-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1H-pyrazol-5-amine

A suspension of 1-benzyl-1H-pyrazol-5-amine (5.0 g),(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)boronic acid (15 g), copperacetate (11 g), pyridine (12 mL) and molecular sieves 4A (10 g) intetrahydrofuran (150 mL) was stirred for 12 hr. The reaction mixture wasdiluted with ethyl acetate, the insoluble material was filtered offthrough celite, and the filtrate was concentrated. The residue waspurified by silica gel column chromatography to give the title compoundas a pale-yellow amorphous solid (4.9 g, 45%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.14 (s, 6H), 0.93 (s, 9H), 5.23 (s, 2H),5.91 (d, J=1.5 Hz, 1H), 6.62-6.84 (m, 4H), 7.04-7.41 (m, 6H), 7.76 (s,1H)

Reference Example 546N-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1H-pyrazol-5-amine

To a suspension of1-benzyl-N-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1H-pyrazol-5-amine(4.9 g) and palladium hydroxide (10 wt %, 5.0 g) in ethanol (22.5mL)-acetic acid (2.5 mL) was added ammonium formate (2.4 g) at 80° C.After stirring at 80° C. for 3 hr, the mixture was allowed to cool,ethyl acetate was added, and the insoluble material was filtered off.Saturated aqueous sodium hydrogen carbonate solution was added to thefiltrate, and the mixture was extracted with ethyl acetate. The organiclayer was washed with water and saturated brine, dried over anhydrousmagnesium sulfate, and concentrated. The residue was purified by silicagel column chromatography to give the title compound as a pale-yellowamorphous solid (2.8 g, 74%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.14 (s, 6H), 0.94 (s, 9H), 5.74 (s, 1H),6.67 (d, J=9.1 Hz, 2H), 7.21 (d, J=8.3 Hz, 2H), 7.50 (s, 1H), 8.07 (s,1H), 11.83 (s, 1H)

Reference Example 5474′-{[4-(4-hydroxyphenyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A solution ofN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1H-pyrazol-5-amine (2.8 g),1,8-diazabicyclo[5.4.0]undec-7-ene (0.30 mL) and ethyl2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (7.0 g) indiethylaniline (15 mL) was stirred at 180° C. for 8 hr. The mixture wasallowed to cool, tetrahydrofuran (5 mL) and tetrabutylammonium fluoride(1.0 M tetrahydrofuran solution, 5 mL) were added, and the mixture wasstirred for 1 hr. To the reaction mixture were added ethyl acetate andsaturated aqueous ammonium chloride solution, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (3.5 g, 79%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.98 (t, J=7.4 Hz, 3H), 1.54-1.71 (m, 2H),2.99-3.09 (m, 2H), 4.02 (s, 2H), 5.43 (d, J=1.9 Hz, 1H), 6.86-7.96 (m,13H), 9.82 (s, 1H)

Reference Example 548 ethyl(4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}phenoxy)acetate

To a solution of4′-{[4-(4-hydroxyphenyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.92 g) in N,N-dimethylformamide (10 mL) were added ethyl bromoacetate(0.66 mL) and cesium carbonate (1.3 g) and the mixture was stirred at70° C. for 15 hr. The mixture was allowed to cool, ethyl acetate andwater were added, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine, dried overanhydrous magnesium sulfate, and concentrated. The residue was purifiedby silica gel column chromatography to give the title compound as apale-yellow amorphous solid (0.82 g, 75%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.98 (t, J=7.4 Hz, 3H), 1.23 (t, J=7.2 Hz,3H), 1.56-1.70 (m, 2H), 2.99-3.10 (m, 2H), 4.02 (s, 2H), 4.19 (q, J=7.1Hz, 2H), 4.87 (s, 2H), 5.42 (d, J=2.3 Hz, 1H), 7.05-7.97 (m, 13H)

Reference Example 5494′-({4-[4-(2-hydroxy-2-methylpropoxy)phenyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of ethyl(4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}phenoxy)acetate(0.30 g) in tetrahydrofuran (3 mL) was added dropwise methylmagnesiumbromide (1 M tetrahydrofuran solution, 2.2 mL) at 0° C., and the mixturewas stirred for 3 hr. To the reaction mixture were added ethyl acetateand then saturated aqueous ammonium chloride solution, and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (0.25 g, 85%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.98 (t, J=7.2 Hz, 3H), 1.23 (s, 6H),1.53-1.72 (m, 2H), 3.00-3.09 (m, 2H), 3.78 (s, 2H), 4.02 (s, 2H), 5.44(d, J=1.9 Hz, 1H), 7.05-7.97 (m, 13H)

Reference Example 5504′-{[4-(4-{[(1R,2S)-2-hydroxy-1-methylpropyl]oxy}phenyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-{[4-(4-hydroxyphenyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.92 g) in N,N-dimethylformamide (10 mL) were addedtrans-2,3-epoxybutane (1.8 mL) and then cesium carbonate (2.0 g), andthe mixture was stirred at 100° C. for 15 hr. The mixture was allowed tocool, to the reaction mixture were added ethyl acetate and thensaturated aqueous ammonium chloride solution, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (0.57 g, 54%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.98 (t, J=7.2 Hz, 3H), 1.11 (d, J=6.4 Hz,3H), 1.21 (d, J=6.4 Hz, 3H), 1.56-1.72 (m, 2H), 3.00-3.09 (m, 2H),3.73-3.86 (m, 1H), 4.02 (s, 2H), 4.28-4.42 (m, 1H), 4.82 (d, J=4.9 Hz,1H), 5.46 (d, J=2.3 Hz, 1H), 7.05-7.97 (m, 13H)

Reference Example 5512-(4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}phenoxy)-N-methoxy-N-methylacetamide

To a solution of ethyl(4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}phenoxy)acetate(0.51 g) in tetrahydrofuran (5 mL) was added 1 M aqueous sodiumhydroxide solution (5 mL) and the mixture was stirred at 60° C. for 1hr. The mixture was allowed to cool, and neutralized with 1 Mhydrochloric acid, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and then with saturated brine, driedover anhydrous magnesium sulfate, and concentrated. The residue wasdissolved in acetonitrile (30 mL), methoxymethylamine hydrochloride(0.27 g), 4-dimethylaminopyridine (0.034 g), diisopropylethylamine (0.81mL), 1-hydroxybenzotriazole (0.16 g) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.36 g)were added and the mixture was stirred for 15 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was extractedwith ethyl acetate. The organic layer was washed with water and thenwith saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (0.44 g, 84%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.98 (t, J=7.2 Hz, 3H), 1.55-1.70 (m, 2H),3.00-3.09 (m, 2H), 3.15 (s, 3H), 3.77 (s, 3H), 4.02 (s, 2H), 4.99 (s,2H), 5.43 (d, J=1.1 Hz, 1H), 6.97-8.07 (m, 13H)

Reference Example 5524′-({4-[4-(2-hydroxypropoxy)phenyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile

To a solution of2-(4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}phenoxy)-N-methoxy-N-methylacetamide(0.44 g) in tetrahydrofuran (4 mL) was added dropwise methylmagnesiumbromide (1 M tetrahydrofuran solution, 1.6 mL) at 0° C., and the mixturewas stirred for 1 hr. Ethyl acetate and then saturated aqueous ammoniumchloride solution were added. The mixture was extracted with ethylacetate, and the organic layer was washed with saturated brine, driedover anhydrous magnesium sulfate, and concentrated. The residue wasdissolved in ethanol (4 mL), and sodium borohydride (0.030 g) was addedat 0° C. After stirring at 0° C. for 30 min, ethyl acetate and thensaturated aqueous ammonium chloride solution were added. The mixture wasextracted with ethyl acetate, and the organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (0.30 g, 73%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.98 (t, J=7.4 Hz, 3H), 1.17 (d, J=6.1 Hz,3H), 1.56-1.71 (m, 2H), 2.99-3.10 (m, 2H), 3.82-4.04 (m, 5H), 4.90 (d,J=1.9 Hz, 1H), 5.44 (d, J=1.9 Hz, 1H), 7.04-7.97 (m, 13H)

Reference Example 553 2-[5-(hydroxymethyl)thiophen-2-yl]benzonitrile

A mixture of 5-bromothiophene-2-carboxyaldehyde (5.00 g),2-cyanophenylboric acid (3.95 g),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),dichloromethane adduct (0.22 g), tetrabutylammonium bromide (0.26 g), 2Maqueous sodium carbonate solution (20 mL) and toluene (200 mL) wasrefluxed under an argon atmosphere overnight. The reaction mixture wasconcentrated, and the residue was dissolved in ethyl acetate. Theobtained ethyl acetate solution was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. To a mixture of the obtained residue, methanol (20 mL)and hydrofuran (20 mL) was gradually added sodium borohydride (0.50 g)at 0° C., and the mixture was stirred at room temperature for 10 min.The reaction mixture was poured into a saturated aqueous potassiumhydrogensulfate solution, and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow solid (2.60g, 46%).

¹H NMR (300 MHz, CDCl₃) δ 1.89 (t, J=6.0, 1H), 4.88 (d, J=6.0, 2H),7.04-7.07 (m, 1H), 7.33-7.43 (m, 1H), 7.48-7.52 (m, 1H), 7.56-7.62 (m,2H), 7.70-7.75 (m, 1H)

Reference Example 554 2-[5-(bromomethyl)thiophen-2-yl]benzonitrile

To a solution (50 mL) of 2-[5-(hydroxymethyl)thiophen-2-yl]benzonitrile(2.60 g) in toluene was added phosphine tribromide (2.60 g) at roomtemperature, and the mixture was stirred at room temperature overnight.The reaction mixture was concentrated, and the residue was dissolved inethyl acetate. The obtained ethyl acetate solution was washed withsaturated aqueous sodium hydrogen carbonate and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (3.20 g, 95%).

¹H NMR (300 MHz, CDCl₃) δ 4.75 (s, 2H), 7.14-7.17 (m, 1H), 7.36-7.43 (m,1H), 7.45-7.49 (m, 1H), 7.57-7.62 (m, 2H), 7.71-7.76 (m, 1H)

Reference Example 555 ethyl2-{[5-(2-cyanophenyl)thiophen-2-yl]methyl}-3-oxohexanoate

To a mixture of 60% sodium hydride in oil (0.71 g) and tetrahydrofuran(20 mL) was added dropwise a mixture of ethyl 3-oxohexanoate (3.65 g) intetrahydrofuran (10 mL) at 0° C., and the mixture was stirred at roomtemperature for 30 min. Then,2-[5-(bromomethyl)thiophen-2-yl]benzonitrile (3.20 g) was added, and themixture was stirred at room temperature overnight. The reaction mixturewas poured into 1 M hydrochloric acid (50 mL), and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless oil (3.30 g, 81%).

¹H NMR (300 MHz, CDCl₃) δ 0.89 (t, J=6.6, 3H), 1.26 (t, J=7.2, 3H),1.54-1.70 (m, 2H), 2.38-2.70 (m, 2H), 3.31-3.48 (m, 2H), 3.85 (t, J=7.5,1H), 4.14-4.28 (m, 2H), 6.85 (d, J=3.6, 1H), 7.32-7.39 (m, 1H), 7.43 (d,J=3.6, 1H), 7.52-7.60 (m, 2H), 7.68-7.74 (m, 1H)

Reference Example 5562-(5-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}thiophen-2-yl)benzonitrile

A mixture of N-(1,4-dioxaspiro[4.5]dec-8-yl)-4H-1,2,4-triazol-3-amine(1.10 g), ethyl2-{[5-(2-cyanophenyl)thiophen-2-yl]methyl}-3-oxohexanoate (3.30 g),1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 mL) and N,N-diethylaniline (20mL) was stirred at 180° C. overnight. The mixture was allowed to cooland poured into 1 M hydrochloric acid (50 mL), and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as apale-yellow oil (0.85 g, 34%).

¹H NMR (300 MHz, CDCl₃) δ 1.11 (t, J=7.2, 3H), 1.70-2.00 (m, 8H),2.88-3.14 (m, 4H), 3.94-4.10 (m, 4H), 4.13 (s, 2H), 5.06-5.22 (m, 1H),6.95 (d, J=3.6, 1H), 7.28-7.38 (m, 1H), 7.46 (d, J=3.6, 1H), 7.52-7.57(m, 2H), 7.67-7.72 (m, 1H), 7.95 (s, 1H)

Reference Example 557 ethyl2-{[6-(2-cyanophenyl)pyridin-3-yl]methyl}-3-oxohexanoate

To a mixture of 60% sodium hydride in oil (1.64 g) and tetrahydrofuran(30 mL) was added dropwise a mixture of ethyl 3-oxohexanoate (8.10 g) intetrahydrofuran (20 mL) at 0° C., and the mixture was stirred at roomtemperature for 30 min. Then,2-[5-(chloromethyl)pyridin-2-yl]benzonitrile (2.25 g) andtetrabutylammonium iodide (1.25 g) were added, and the mixture wasstirred at room temperature overnight. The reaction mixture was pouredinto 1 M hydrochloric acid (50 mL), and the mixture was extracted withethyl acetate. The ethyl acetate layer was washed with saturated brine,and dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography to give the title compound as a yellow oil (2.20g, 62%).

¹H NMR (300 MHz, CDCl₃) δ 0.87 (t, J=7.2, 3H), 1.23 (t, J=7.2, 3H),1.52-1.70 (m, 2H), 2.36-2.68 (m, 2H), 3.15-3.30 (m, 2H), 3.81 (t, J=7.5,1H), 4.10-4.24 (m, 2H), 7.44-7.52 (m, 1H), 7.62-7.72 (m, 3H), 7.76-7.86(m, 2H), 8.57-8.64 (m, 1H)

Reference Example 5581-benzyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine

To a solution of 1-benzyl-1H-pyrazol-5-amine (2.09 g) in acetic acid (20mL) was added tetrahydro-4H-pyran-4-one (1.25 g), and the mixture wasstirred at room temperature for 30 min. After stirring, sodiumtriacetoxyborohydride (3.90 g) was added at room temperature, and themixture was stirred overnight. Acetic acid was evaporated under reducedpressure and ethyl acetate and water were added to the residue. Themixture was neutralized with sodium hydrogen carbonate, and the mixturewas extracted with ethyl acetate. The ethyl acetate layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas a pale-yellow oil (3.00 g, 97%).

¹H NMR (300 MHz, CDCl₃) δ 1.34-1.40 (m, 2H), 1.84-1.94 (m, 2H),3.34-3.46 (m, 2H), 3.78-3.92 (m, 3H), 5.19 (s, 2H), 5.52 (d, J=2.1, 1H),7.09-7.16 (m, 2H), 7.25-7.36 (m, 4H)

Reference Example 559 N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine

A mixture of 1-benzyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine(3.00 g), palladium-carbon (10 wt %, 2.33 g) and ethanol (100 mL) wasstirred under a hydrogen atmosphere at 50° C. and 5 atm for 9 hr. Theinsoluble material was filtered off, and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (1.70 g,87%).

¹H NMR (300 MHz, CDCl₃) δ 1.42-1.56 (m, 2H), 2.01-2.10 (m, 2H),3.42-3.64 (m, 4H), 3.74-4.03 (m, 2H), 6.64 (d, J=2.4, 1H), 7.34 (d,J=2.4, 1H), 9.10 (br. s, 1H)

Reference Example 5604′-{[5-oxo-7-propyl-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine (1.00 g),ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (4.20 g),1,8-diazabicyclo[5.4.0]undec-7-ene (0.9 mL) and N,N-diethylaniline (10mL) was stirred at 180° C. overnight, allowed to cool, and poured into 1M hydrochloric acid (50 mL), and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (2.39 g,88%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=6.9, 3H), 1.63-1.82 (m, 4H),2.52-2.68 (m, 2H), 3.04-3.12 (m, 2H), 3.48-3.62 (m, 2H), 4.02 (s, 2H),4.08-4.16 (m, 2H), 5.33 (br. s, 1H), 6.13 (d, J=2.1, 1H), 7.35-7.52 (m,6H), 7.57-7.65 (m, 1H), 7.71-7.76 (m, 2H)

Reference Example 561 methyl2-{[6-(2-cyanophenyl)pyridin-3-yl]methyl}-3-oxoheptanoate

To a mixture of 60% sodium hydride in oil (3.27 g) and tetrahydrofuran(50 mL) was added dropwise a mixture of methyl 3-oxoheptanoate (16.18 g)in tetrahydrofuran (50 mL) at 0° C., and the mixture was stirred at roomtemperature for 30 min. Then,2-[5-(chloromethyl)pyridin-2-yl]benzonitrile (4.45 g) andtetrabutylammonium iodide (2.27 g) were added, and the mixture wasstirred at room temperature overnight. The reaction mixture was pouredinto 1 M hydrochloric acid (70 mL), and the mixture was extracted withethyl acetate. The ethyl acetate layer was washed with saturated brine,and dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography to give the title compound as a yellow oil (0.88g, 12%).

¹H NMR (300 MHz, CDCl₃) δ 0.87 (t, J=7.2, 3H), 1.18-1.32 (m, 2H),1.48-1.62 (m, 2H), 2.34-2.68 (m, 2H), 3.15-3.30 (m, 2H), 3.72 (s, 3H),3.84 (t, J=7.5, 1H), 7.44-7.53 (m, 1H), 7.62-7.72 (m, 3H), 7.76-7.86 (m,2H), 8.57-8.63 (m, 1H)

Reference Example 5624′-(hydroxymethyl)-2′-methylbiphenyl-2-carbonitrile

A mixture of 4-bromo-3-methylbenzylalcohol (15.16 g), 2-cyanophenylboricacid (14.80 g),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),dichloromethane adduct (3.08 g), tetrabutylammonium bromide (1.22 g), 2Maqueous sodium carbonate solution (75 mL) and toluene (300 mL) wasrefluxed under an argon atmosphere for 30 hr. The reaction mixture wasconcentrated, and the residue was dissolved in ethyl acetate. Theobtained ethyl acetate solution was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow oil (4.12 g,24%).

¹H NMR (300 MHz, CDCl₃) δ 2.20 (s, 3H), 4.73 (d, J=5.1, 2H), 7.15-7.50(m, 5H), 7.57-7.67 (m, 1H), 7.70-7.78 (m, 1H)

Reference Example 563 ethyl2-[(2′-cyano-2-methylbiphenyl-4-yl)methyl]-3-oxohexanoate

To a solution (15 mL) of4′-(hydroxymethyl)-2′-methylbiphenyl-2-carbonitrile (4.12 g) in toluenewas added phosphine tribromide (6.00 g) at room temperature, and themixture was stirred at room temperature overnight. The reaction mixturewas concentrated, and the residue was dissolved in ethyl acetate. Theobtained ethyl acetate solution was washed with saturated aqueous sodiumhydrogen carbonate and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow oil (5.08 g,96%). To a mixture of 60% sodium hydride in oil (1.10 g) andtetrahydrofuran (20 mL) was added dropwise a mixture of ethyl3-oxohexanoate (5.62 g) in tetrahydrofuran (20 mL) at 0° C., and themixture was stirred at room temperature for 30 min. Then,4′-(bromomethyl)-2′-methylbiphenyl-2-carbonitrile (5.08 g) was added,and the mixture was stirred at room temperature overnight. The reactionmixture was poured into 1 M hydrochloric acid (50 mL), and the mixturewas extracted with ethyl acetate. The ethyl acetate layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless oil (4.53 g, 70%).

¹H NMR (300 MHz, CDCl₃) δ 0.86 (t, J=7.5, 3H), 1.23 (t, J=7.2, 3H),1.50-1.66 (m, 2H), 2.15 (s, 3H), 2.30-2.64 (m, 2H), 3.10-3.26 (m, 2H),3.82 (t, J=7.5, 1H), 4.16 (q, J=7.2, 2H), 7.04-7.16 (m, 3H), 7.28-7.36(m, 1H), 7.38-7.48 (m, 1H), 7.57-7.65 (m, 1H), 7.68-7.76 (m, 1H)

Reference Example 564 4′-formyl-2′-nitrobiphenyl-2-carbonitrile

A mixture of 4-bromo-3-nitrobenzaldehyde (10.0 g), 2-cyanophenylboricacid (8.25 g),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),dichloromethane adduct (3.45 g), tetrabutylammonium bromide (1.36 g), 2Maqueous sodium carbonate solution (40 mL) and toluene (400 mL) wasrefluxed under an argon atmosphere for 3 days. The reaction mixture wasconcentrated, and the residue was dissolved in ethyl acetate. Theobtained ethyl acetate solution was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow solid (5.15g, 40%).

¹H NMR (300 MHz, CDCl₃) δ 7.34-7.42 (m, 1H), 7.54-7.85 (m, 4H),8.21-8.26 (m, 1H), 8.64 (d, J=1.5, 1H), 10.16 (s, 1H)

Reference Example 565 4′-(hydroxymethyl)-2′-nitrobiphenyl-2-carbonitrile

To a mixture of 4′-formyl-2′-nitrobiphenyl-2-carbonitrile (5.15 g),methanol (30 mL) and hydrofuran (30 mL) was gradually added sodiumborohydride (0.40 g) at 0° C., and the mixture was stirred at roomtemperature for 30 min. The reaction mixture was poured into 1 Mhydrochloric acid (20 mL), and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow oil (3.62 g,70%).

¹H NMR (300 MHz, CDCl₃) δ 4.87 (s, 2H), 7.32-7.83 (m, 6H), 8.12-8.20 (m,1H)

Reference Example 566 ethyl2-[(2′-cyano-2-nitrobiphenyl-4-yl)methyl]-3-oxohexanoate

To a solution (15 mL) of4′-(hydroxymethyl)-2′-nitrobiphenyl-2-carbonitrile (3.62 g) in toluenewas added phosphine tribromide (4.63 g) at room temperature, and themixture was stirred at room temperature overnight. The reaction mixturewas concentrated, and the residue was dissolved in ethyl acetate. Theobtained ethyl acetate solution was washed with saturated aqueous sodiumhydrogen carbonate and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give 4′-(bromomethyl)-2′-nitrobiphenyl-2-carbonitrileas a pale-yellow oil. To a mixture of 60% sodium hydride in oil (0.85 g)and tetrahydrofuran (20 mL) was added dropwise a mixture of ethyl3-oxohexanoate (4.50 g) in tetrahydrofuran (10 mL) at 0° C., and themixture was stirred at room temperature for 30 min. Then, theaforementioned 4′-(bromomethyl)-2′-nitrobiphenyl-2-carbonitrile wasadded, and the mixture was stirred at room temperature overnight. Thereaction mixture was poured into 1 M hydrochloric acid (30 mL), and themixture was extracted with ethyl acetate. The ethyl acetate layer waswashed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas a yellow oil (4.60 g, 82%).

¹H NMR (300 MHz, CDCl₃) δ 0.89 (t, J=7.5, 3H), 1.25 (t, J=7.2, 3H),1.52-1.70 (m, 2H), 2.36-2.68 (m, 2H), 3.22-3.40 (m, 2H), 3.85 (t, J=6.9,1H), 4.19 (q, J=7.2, 2H), 7.28-7.38 (m, 2H), 7.46-7.68 (m, 3H),7.72-7.80 (m, 1H), 7.94-8.02 (m, 1H)

Reference Example 5674′-{[4-(4-hydroxyphenyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(6.00 g), 4-isopropoxyphenylboric acid (5.85 g), copper(II) acetate(5.90 g), pyridine (18 mL), triethylamine (9 mL), molecular sieves 4A(18.0 g) and tetrahydrofuran (100 mL) was stirred at room temperaturefor 1 day. Ethyl acetate (100 mL) was added to the reaction mixture, themixture was stirred at room temperature for 1 hr, and the insolublematerial was filtered off. The filtrate was concentrated, and theresidue was purified by silica gel column chromatography to give4′-({4-[4-(1-methylethoxy)phenyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrileas a colorless solid (6.53 g, 80%). A mixture of4′-({4-[4-(1-methylethoxy)phenyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(6.53 g) and 25% hydrobromic acid-acetic acid solution (10 mL) wasstirred under refluxing for 2 hr. The reaction mixture was concentrated,and the residue was dissolved in ethyl acetate. The obtained ethylacetate solution was washed with saturated aqueous sodium hydrogencarbonate and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (4.38 g, 73%).

¹H NMR (300 MHz, CDCl₃) δ 1.12 (t, J=7.2, 3H), 1.73-1.88 (m, 2H),3.08-3.18 (m, 2H), 4.07 (s, 2H), 6.69-6.77 (m, 2H), 7.08-7.16 (m, 2H),7.37-7.52 (m, 5H), 7.57-7.66 (m, 2H), 7.71-7.76 (m, 1H), 7.93 (s, 1H)

Reference Example 568 methyl2-(4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}phenoxy)-2-methylpropanoate

A mixture of4′-{[4-(4-hydroxyphenyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(3.70 g), methyl 2-bromo-2-methylpropanoate (7.30 g), cesium carbonate(13.07 g) and N,N-dimethylformamide (20 mL) was stirred at 80° C.overnight. The reaction mixture was poured into 1 M hydrochloric acid(40 mL), and the mixture was extracted with ethyl acetate. The ethylacetate layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless oil (4.50 g, quantitative).

¹H NMR (300 MHz, CDCl₃) δ 1.11 (t, J=7.5, 3H), 1.64 (s, 6H), 1.73-1.88(m, 2H), 3.08-3.18 (m, 2H), 3.76 (s, 3H), 4.05 (s, 2H), 6.89-6.97 (m,2H), 7.25-7.33 (m, 2H), 7.38-7.50 (m, 6H), 7.58-7.65 (m, 1H), 7.70-7.76(m, 1H), 7.86 (s, 1H)

Reference Example 5694′-{[7-butyl-4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile

A mixture of methyl2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxoheptanoate (6.55 g),N-(1,4-dioxaspiro[4.5]dec-8-yl)-4H-1,2,4-triazol-3-amine (2.00 g),1,8-diazabicyclo[5.4.0]undec-7-ene (0.5 mL) and N,N-diethylaniline (20mL) was stirred at 180° C. overnight, allowed to cool, and poured into 1M hydrochloric acid (100 mL), and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow oil (2.88 g,60%).

¹H NMR (300 MHz, CDCl₃) δ 0.95 (t, J=7.2, 3H), 1.40-2.00 (m, 10H),2.88-3.14 (m, 4H), 3.94-4.10 (m, 6H), 5.06-5.22 (m, 1H), 7.20-7.52 (m,5H), 7.59-7.66 (m, 1H), 7.72-7.78 (m, 1H), 7.95 (s, 1H)

Reference Example 5704′-{[7-butyl-5-oxo-4-(4-oxocyclohexyl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile

A mixture of4′-{[7-butyl-4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile(2.88 g), 3N hydrochloric acid (20 mL) and tetrahydrofuran (20 mL) wasstirred under refluxing for 16 hr. The reaction mixture was neutralizedwith 1 M aqueous sodium hydroxide solution (60 mL), and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless oil (2.61 g, 99%).

¹H NMR (300 MHz, CDCl₃) δ 0.96 (t, J=7.2, 3H), 1.40-1.74 (m, 4H),2.00-2.16 (m, 2H), 2.50-2.62 (m, 4H), 3.00-3.20 (m, 4H), 4.03 (s, 2H),5.46-5.62 (m, 1H), 7.22-7.50 (m, 5H), 7.59-7.68 (m, 1H), 7.72-7.78 (m,1H), 7.90 (s, 1H)

Reference Example 5714′-{[7-butyl-4-(trans-4-hydroxycyclohexyl)-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile

To a mixture of4′-{[7-butyl-5-oxo-4-(4-oxocyclohexyl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile(2.61 g), tetrahydrofuran (10 mL) and methanol (10 mL) was added sodiumborohydride (0.15 g) at 0° C., and the mixture was stirred at roomtemperature for 1 hr. After evaporation of the solvent under reducedpressure, the residue was extracted with water and ethyl acetate. Theobtained ethyl acetate layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless oil (2.14 g,82%).

¹H NMR (300 MHz, CDCl₃) δ 0.95 (t, J=7.2, 3H), 1.40-1.84 (m, 8H),2.06-2.20 (m, 2H), 2.64-2.84 (m, 2H), 3.00-3.14 (m, 2H), 3.74-3.88 (m,1H), 4.01 (s, 2H), 4.96-5.14 (m, 1H), 7.20-7.48 (m, 5H), 7.59-7.68 (m,1H), 7.72-7.78 (m, 1H), 7.90 (s, 1H)

Reference Example 572 ethyl[(trans-4-{7-butyl-6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate

To a mixture of4′-{[7-butyl-4-(trans-4-hydroxycyclohexyl)-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile(2.14 g), rhodium(I) acetate (0.57 g) and toluene (30 mL) was addeddropwise a solution of ethyl diazoacetate (2.30 g) in toluene (10 mL) at70° C., and the mixture was stirred at the same temperature for 30 min.The reaction mixture was poured into water, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless oil (1.24 g, 49%).

¹H NMR (300 MHz, CDCl₃) δ 0.95 (t, J=7.5, 3H), 1.30 (t, J=7.2, 3H),1.40-1.90 (m, 8H), 2.14-2.38 (m, 2H), 2.60-2.78 (m, 2H), 3.00-3.10 (m,2H), 3.44-3.60 (m, 1H), 4.01 (s, 2H), 4.13 (s, 2H), 4.22 (q, J=7.2, 2H),4.96-5.14 (m, 1H), 7.21-7.50 (m, 5H), 7.59-7.66 (m, 1H), 7.72-7.78 (m,1H), 7.90 (s, 1H)

Reference Example 5734′-({7-butyl-4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)-3′-fluorobiphenyl-2-carbonitrile

Ethyl[(trans-4-{7-butyl-6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate(1.24 g) was dissolved in tetrahydrofuran (15 mL), and methylmagnesiumbromide (1.0 M tetrahydrofuran solution, 6.5 mL) was added at roomtemperature. The reaction mixture was stirred for 1 hr, 1 N hydrochloricacid was added, and the mixture was extracted with ethyl acetate. Theobtained ethyl acetate layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography to give the title compound as a colorless oil (0.76 g,63%).

¹H NMR (300 MHz, CDCl₃) δ 0.95 (t, J=7.2, 3H), 1.20 (s, 6H), 1.36-1.86(m, 8H), 2.14-2.24 (m, 2H), 2.60-2.80 (m, 2H), 3.02-3.10 (m, 2H), 3.30(s, 2H), 3.38-3.51 (m, 1H), 4.01 (s, 2H), 5.00-5.14 (m, 1H), 7.21-7.28(m, 2H), 7.32-7.49 (m, 3H), 7.59-7.67 (m, 1H), 7.72-7.78 (m, 1H), 7.90(s, 1H)

Reference Example 5741-benzyl-N-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazol-5-amine

To a solution of 1-benzyl-1H-pyrazol-5-amine (43.3 g) in acetic acid(500 mL) was added 1,4-dioxaspiro[4.5]decan-8-one (47 g) at roomtemperature, and the mixture was stirred for 30 min. Sodiumtriacetoxyborohydride (64 g) was added by small portions at roomtemperature, and the mixture was stirred for 18 hr. Acetic acid wasevaporated, and ethyl acetate and water were added to the residue. Themixture was neutralized with sodium hydrogen carbonate, and the mixturewas extracted with ethyl acetate. The organic layer was washed withwater and brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was dissolved in a small amount of ethylacetate, and the mixture was crystallized using diisopropyl ether. Theresulting solid was collected by filtration, washed with diisopropylether, and dried under reduced pressure to give the title compound as apale-yellow solid (61 g, 78%).

¹H NMR (300 MHz, DMSO-d₆) δ 1.38-1.87 (m, 8H), 3.00-3.16 (m, 1H), 3.84(s, 4H), 5.14 (s, 2H), 5.26 (d, J=7.2 Hz, 1H), 5.40 (d, J=1.9 Hz, 1H),7.02-7.33 (m, 6H)

Reference Example 575 N-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazol-5-amine

To a suspension of1-benzyl-N-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazol-5-amine (38 g) andpalladium hydroxide (10 wt %, 11.4 g) in ethanol (200 mL)-acetic acid(40 mL) was added ammonium formate (32 g) by small portions at 80° C.After stirring at 80° C. for 4 hr, the mixture was allowed to cool toroom temperature, ethyl acetate was added, and the insoluble materialwas filtered off. Saturated aqueous sodium hydrogen carbonate was addedto the filtrate, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and brine, dried over anhydrousmagnesium sulfate, and concentrated. The residue was crystallized usingethyl acetate, and the resulting solid was collected by filtration,washed with diisopropyl ether, and dried under reduced pressure to givethe title compound as a pale-yellow solid (22 g, 82%).

¹H NMR (300 MHz, DMSO-d₆) δ 1.34-1.92 (m, 8H), 3.11-3.29 (m, 1H), 3.84(s, 4H), 4.68-5.08 (m, 1H), 5.40 (br. s., 1H), 7.30 (br. s., 1H), 11.39(br. s., 1H)

Reference Example 576 ethyl2-[1-(2′-cyanobiphenyl-4-yl)ethyl]-3-oxohexanoate

To a mixture of 60% sodium hydride in oil (0.82 g) and tetrahydrofuran(20 mL) was added dropwise a mixture of ethyl 3-oxohexanoate (4.35 g) intetrahydrofuran (20 mL) at 0° C., and the mixture was stirred at roomtemperature for 30 min. Then, 4′-(1-bromoethyl)biphenyl-2-carbonitrile(3.93 g) was added, and the mixture was stirred at 50° C. overnight. Thereaction mixture was poured into 1 M hydrochloric acid (30 mL), and themixture was extracted with ethyl acetate. The ethyl acetate layer waswashed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless oil (4.70 g, 94%).

¹H NMR (300 MHz, CDCl₃) δ 0.64-1.75 (m, 11H), 2.04-2.70 (m, 2H),3.58-4.30 (m, 4H), 7.28-7.52 (m, 6H), 7.58-7.66 (m, 1H), 7.70-7.78 (m,1H)

Reference Example 5774′-{1-[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]ethyl}biphenyl-2-carbonitrile

A mixture of ethyl 2-[1-(2′-cyanobiphenyl-4-yl)ethyl]-3-oxohexanoate(4.80 g), N-(1,4-dioxaspiro[4.5]dec-8-yl)-4H-1,2,4-triazol-3-amine (1.50g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 mL) and N,N-diethylaniline(20 mL) was stirred at 180° C. overnight, allowed to cool and pouredinto 1 M hydrochloric acid (100 mL), and the mixture was extracted withethyl acetate. The ethyl acetate layer was washed with saturated brine,and dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography to give the title compound as a pale-yellow oil(1.50 g, 43%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.5, 3H), 1.40-1.94 (m, 11H),2.84-3.10 (m, 4H), 3.92-4.06 (m, 4H), 4.52-4.66 (m, 1H), 5.02-5.16 (m,1H), 7.37-7.54 (m, 6H), 7.59-7.66 (m, 1H), 7.71-7.77 (m, 1H), 7.93 (s,1H)

Reference Example 5784′-{1-[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]ethyl}biphenyl-2-carbonitrile

A mixture of4′-{1-[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]ethyl}biphenyl-2-carbonitrile(1.50 g), 3N hydrochloric acid (30 mL) and tetrahydrofuran (20 mL) wasstirred under refluxing for 15 hr. The reaction mixture was neutralizedwith 1 M aqueous sodium hydroxide solution (90 mL), and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless oil (1.38 g, quantitative).

¹H NMR (300 MHz, CDCl₃) δ 1.03 (t, J=7.2, 3H), 1.62-2.12 (m, 7H),2.42-2.62 (m, 4H), 2.90-3.20 (m, 4H), 4.52-4.64 (m, 1H), 5.42-5.60 (m,1H), 7.38-7.57 (m, 6H), 7.59-7.66 (m, 1H), 7.72-7.78 (m, 1H), 7.88 (s,1H)

Reference Example 5794′-{1-[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]ethyl}biphenyl-2-carbonitrile

To a mixture of4′-{1-[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]ethyl}biphenyl-2-carbonitrile(1.38 g), tetrahydrofuran (15 mL) and methanol (10 mL) was added sodiumborohydride (0.50 g) at 0° C., and the mixture was stirred at roomtemperature for 30 min. After evaporation of the solvent under reducedpressure, the residue was extracted with water and ethyl acetate. Theobtained ethyl acetate layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless oil (1.24 g,89%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.2, 3H), 1.40-2.16 (m, 12H),2.62-3.10 (m, 4H), 3.72-3.88 (m, 1H), 4.52-4.66 (m, 1H), 4.94-5.10 (m,1H), 7.38-7.54 (m, 6H), 7.59-7.66 (m, 1H), 7.72-7.76 (m, 1H), 7.89 (s,1H)

Reference Example 580 ethyl[(trans-4-{6-[1-(2′-cyanobiphenyl-4-yl)ethyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate

To a mixture of4′-{1-[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]ethyl}biphenyl-2-carbonitrile(1.24 g), rhodium(I) acetate (0.34 g) and toluene (20 mL) was addeddropwise a solution of ethyl diazoacetate (1.38 g) in toluene (10 mL) at70° C., and the mixture was stirred at the same temperature for 30 min.The reaction mixture was poured into water, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless oil (0.70 g, 48%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.5, 3H), 1.28 (t, J=7.2, 3H),1.40-2.16 (m, 11H), 2.56-2.78 (m, 2H), 2.88-3.06 (m, 2H), 3.40-3.56 (m,1H), 4.08-4.28 (m, 4H), 4.50-4.64 (m, 1H), 4.96-5.06 (m, 1H), 7.18-7.30(m, 1H), 7.38-7.54 (m, 5H), 7.58-7.66 (m, 1H), 7.71-7.76 (m, 1H), 7.88(s, 1H)

Reference Example 5814′-(1-{4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}ethyl)biphenyl-2-carbonitrile

Ethyl[(trans-4-{6-[1-(2′-cyanobiphenyl-4-yl)ethyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate(0.70 g) was dissolved in tetrahydrofuran (10 mL), and methylmagnesiumbromide (1.0 M tetrahydrofuran solution, 3.6 mL) was added at 0° C. Thereaction mixture was stirred for 30 min, 1 N hydrochloric acid wasadded, and the mixture was extracted with ethyl acetate. The obtainedethyl acetate layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography to give the title compound as a colorless oil (0.39 g,57%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.5, 3H), 1.20 (s, 6H), 1.24-1.86(m, 10H), 2.10-2.24 (m, 2H), 2.58-2.76 (m, 2H), 2.88-3.10 (m, 2H), 3.29(s, 2H), 3.36-3.51 (m, 1H), 4.52-4.66 (m, 1H), 4.94-5.10 (m, 1H),7.38-7.54 (m, 6H), 7.59-7.66 (m, 1H), 7.71-7.77 (m, 1H), 7.88 (s, 1H)

Reference Example 5824′-(hydroxymethyl)-2′-methylbiphenyl-2-carbonitrile

A mixture of 4-bromo-3-methylbenzylalcohol (15.16 g), 2-cyanophenylboricacid (14.80 g),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),dichloromethane adduct (3.08 g), tetrabutylammonium bromide (1.22 g), 2Maqueous sodium carbonate solution (75 mL) and toluene (300 mL) wasrefluxed under an argon atmosphere for 30 hr. The reaction mixture wasconcentrated, and the residue was dissolved in ethyl acetate. Theobtained ethyl acetate solution was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow oil (4.12 g,24%).

¹H NMR (300 MHz, CDCl₃) δ 2.20 (s, 3H), 4.73 (d, J=5.1, 2H), 7.15-7.50(m, 5H), 7.57-7.67 (m, 1H), 7.70-7.78 (m, 1H)

Reference Example 5834′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-2′-methylbiphenyl-2-carbonitrile

A mixture of ethyl2-[(2′-cyano-2-methylbiphenyl-4-yl)methyl]-3-oxohexanoate (3.00 g),N-(1,4-dioxaspiro[4.5]dec-8-yl)-3-methyl-1H-1,2,4-triazol-5-amine (1.00g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.3 mL) and N,N-diethylaniline(10 mL) was stirred at 180° C. overnight, allowed to cool and pouredinto 1 M hydrochloric acid (50 mL), and the mixture was extracted withethyl acetate. The ethyl acetate layer was washed with saturated brine,and dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography to give the title compound as a brown oil (1.20 g,53%).

¹H NMR (300 MHz, CDCl₃) δ 1.04 (t, J=7.2, 3H), 1.56-1.95 (m, 8H), 2.14(s, 3H), 2.44 (s, 3H), 2.88-3.08 (m, 4H), 3.90-4.06 (m, 6H), 4.98-5.12(m, 1H), 7.06-7.19 (m, 3H), 7.30-7.46 (m, 2H), 7.56-7.64 (m, 1H),7.68-7.75 (m, 1H)

Reference Example 5842′-methyl-4′-{[2-methyl-5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-2′-methylbiphenyl-2-carbonitrile(1.20 g), 3N hydrochloric acid (15 mL) and tetrahydrofuran (15 mL) wasstirred under refluxing for 15 hr. The reaction mixture was neutralizedwith 1 M aqueous sodium hydroxide solution (45 mL), and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as apale-yellow oil (1.10 g, quantitative).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.2, 3H), 1.50-2.20 (m, 7H), 2.42(s, 3H), 2.50-2.62 (m, 4H), 2.92-3.22 (m, 4H), 3.96 (s, 2H), 5.44-5.60(m, 1H), 7.08-7.19 (m, 3H), 7.30-7.48 (m, 2H), 7.56-7.65 (m, 1H),7.68-7.76 (m, 1H)

Reference Example 5854′-{[4-(trans-4-hydroxycyclohexyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-2′-methylbiphenyl-2-carbonitrile

To a mixture of2′-methyl-4′-{[2-methyl-5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(1.10 g), tetrahydrofuran (10 mL) and methanol (10 mL) was added sodiumborohydride (0.05 g) at 0° C., and the mixture was stirred at roomtemperature for 30 min. After evaporation of the solvent under reducedpressure, the residue was extracted with water and ethyl acetate. Theobtained ethyl acetate layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless oil (1.01 g,91%).

¹H NMR (300 MHz, CDCl₃) δ 1.05 (t, J=7.5, 3H), 1.42-2.20 (m, 12H), 2.44(s, 3H), 2.67-3.04 (m, 4H), 3.74-3.90 (m, 1H), 3.94 (s, 2H), 4.92-5.08(m, 1H), 7.08-7.18 (m, 3H), 7.30-7.46 (m, 2H), 7.56-7.64 (m, 1H),7.68-7.74 (m, 1H)

Reference Example 586 ethyl[(trans-4-{6-[(2′-cyano-2-methylbiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate

To a mixture of4′-{[4-(trans-4-hydroxycyclohexyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-2′-methylbiphenyl-2-carbonitrile(1.01 g), rhodium(I) acetate (0.30 g) and toluene (20 mL) was addeddropwise a solution of ethyl diazoacetate (1.20 g) in toluene (10 mL) at70° C., and the mixture was stirred at the same temperature for 30 min.The reaction mixture was poured into water, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless oil (0.71 g, 60%).

¹H NMR (300 MHz, CDCl₃) δ 1.04 (t, J=7.2, 3H), 1.30 (t, J=7.2, 3H),1.42-2.30 (m, 11H), 2.43 (s, 3H), 2.64-3.06 (m, 4H), 3.46-3.60 (m, 1H),3.94 (s, 2H), 4.08-4.30 (m, 4H), 4.92-5.08 (m, 1H), 7.08-7.20 (m, 3H),7.31-7.46 (m, 2H), 7.56-7.64 (m, 1H), 7.68-7.74 (m, 1H)

Reference Example 587 N-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazol-5-amine

A solution of 1H-pyrazol-3-amine (10.0 g) and1,4-dioxaspiro[4.5]decan-8-one (20.7 g) in methanol (30 mL) was stirredat room temperature for 30 min. After stirring, a solution of sodiumtetrahydroborate (3.6 g) in 1 M sodium hydroxide (30 mL) was addeddropwise at 0° C. After warming to room temperature, the mixture wasstirred for 4 hr, 1 M hydrochloric acid (100 mL) was added dropwise at0° C., and the mixture was stirred for 1 hr. The resulting solid wascollected by filtration, washed with water, and dried by heating underreduced pressure to give the title compound as a pale-yellow solid (17.2g, 64%).

¹H NMR (300 MHz, DMSO-d₆) δ 1.34-1.92 (m, 8H), 3.11-3.29 (m, 1H), 3.84(s, 4H), 4.68-5.08 (m, 1H), 5.40 (br. s., 1H), 7.30 (br. s., 1H), 11.39(br. s., 1H)

Reference Example 588 ethyl2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate

To a mixture of 3′-fluoro-4′-methylbiphenyl-2-carbonitrile (110 g),N-bromosuccinimide (97.3 g) and benzotrifluoride (1.0 L) was addedazobisisobutyronitrile (1.71 g), and the mixture was heated to aninternal temperature of 78° C. and stirred for 16 hr. The reactionmixture was cooled to around 40° C., and the insoluble material wasremoved to give a solution of4′-(bromomethyl)-3′-fluorobiphenyl-2-carbonitrile in benzotrifluoride.To a suspension of sodium hydride (60% in oil, 25 g) in tetrahydrofuran(750 mL) was added dropwise a solution of ethyl 3-oxohexanoate (164 g)in tetrahydrofuran (250 mL) at 0° C. The reaction mixture was stirred atroom temperature for 1 hr, and a solution of4′-(bromomethyl)-3′-fluorobiphenyl-2-carbonitrile in benzotrifluorideabove mentioned was added at 0° C. The reaction mixture was furtherstirred at room temperature for 16 hr, and added to 1 M hydrochloricacid (1.0 L), and the obtained mixture was concentrated under reducedpressure. The obtained mixture was extracted with ethyl acetate, and theobtained extract was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the obtained residue was purified by silica gel columnchromatography to give the title compound as a colorless oil (145 g,76%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.80 (t, J=7.3 Hz, 3H), 1.10 (t, J=7.2 Hz,3H), 1.40-1.54 (m, 2H), 2.44-2.61 (m, 2H), 3.05-3.22 (m, 2H), 3.98-4.13(m, 3H), 7.32-7.48 (m, 3H), 7.53-7.65 (m, 2H), 7.75-7.83 (m, 1H), 7.96(d, J=7.5 Hz, 1H)

Example 12,4-dimethyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.77 g), sodium hydrogencarbonate (2.84 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-[(2,4-dimethyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.67 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, and the mixture waswashed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was dissolved in tetrahydrofuran (15 mL).N,N′-Carbonyldiimidazole (0.33 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.28 mL) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, and the mixture was washed with saturatedaqueous potassium hydrogensulfate solution and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.41 g, 53%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.3, 3H), 1.60 (d, J=7.7, 2H),2.36 (s, 3H), 2.85-3.04 (m, 2H), 3.52 (s, 3H), 3.99 (s, 2H), 7.35-7.43(m, 2H), 7.44-7.63 (m, 4H), 7.76 (dd, J=7.7, 1.3, 1H), 7.84-7.95 (m, 1H)

Example 24-(2,2-dimethylpropyl)-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.8 g), 1-iodo-2,2-dimethylpropane (0.79 mL), cesium carbonate (1.3 g)and N,N-dimethylacetamide (10 mL) was stirred at 130° C. for 2 hr. Thereaction mixture was diluted with ethyl acetate, and the mixture waswashed with 5% aqueous potassium hydrogensulfate solution and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The residue obtained by silicagel column chromatography was dissolved in dimethyl sulfoxide (5 mL),and the mixture was added to a mixture of hydroxylammonium chloride(0.38 g), sodium hydrogen carbonate (0.88 g) and dimethyl sulfoxide (10mL), which had been stirred in advance at 40° C. for 30 min. Thereaction mixture was stirred at 90° C. for 16 hr, and diluted with ethylacetate, and the mixture was washed with water and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography, and dissolved in tetrahydrofuran (15mL). N,N′-Carbonyldiimidazole (0.16 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, and the mixture was washed with saturatedaqueous potassium hydrogensulfate solution and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.2 g, 20%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.88-0.98 (m, 12H), 1.44-1.66 (m, 2H), 2.33(s, 3H), 2.83-2.97 (m, 2H), 3.95 (s, 2H), 4.01 (s, 2H), 7.17-7.24 (m,2H), 7.24-7.32 (m, 2H), 7.52 (dd, J=17.2, 7.8, 2H), 7.60-7.75 (m, 2H),12.37 (s, 1H)

Example 32-methyl-4-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.34 g), sodium hydrogencarbonate (0.54 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[2-methyl-4-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.17 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, and the mixture waswashed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was dissolved in tetrahydrofuran (10 mL).N,N′-Carbonyldiimidazole (0.062 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.052 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, and the mixture was washed withsaturated aqueous potassium hydrogensulfate solution and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.094 g, 50%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.3 Hz, 3H), 1.42 (d, J=6.2 Hz,3H), 1.50-1.72 (m, 2H), 2.26 (s, 3H), 2.76-2.99 (m, 3H), 3.35-3.45 (m,1H), 3.96 (s, 2H), 4.90-5.14 (m, 1H), 6.83 (d, J=8.5 Hz, 1H), 7.14 (dd,J=8.4, 2.2 Hz, 1H), 7.20-7.27 (m, 3H), 7.29-7.39 (m, 2H), 7.42-7.58 (m,2H), 7.60-7.75 (m, 2H), 12.40 (s, 1H)

Example 44-(4-fluorobenzyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.3 g), sodium hydrogencarbonate (2 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for30 min,4′-{[4-(4-fluorobenzyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.58 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.24 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.24 g,36%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.4, 3H), 1.43-1.70 (m, 2H),2.85-3.05 (m, 2H), 3.98 (s, 2H), 5.28 (s, 2H), 7.07-7.26 (m, 4H),7.27-7.35 (m, 2H), 7.39-7.61 (m, 4H), 7.62-7.73 (m, 2H), 8.21 (s, 1H),12.40 (s, 1H)

Example 54-(4-fluorobenzyl)-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.2 g), sodium hydrogencarbonate (1.9 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[2-methyl-4-(4-fluorobenzyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.56 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.22 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.19 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.26 g,41%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.4, 3H), 1.47-1.64 (m, 2H), 2.35(s, 3H), 2.84-3.02 (m, 2H), 3.96 (s, 2H), 5.25 (s, 2H), 7.11-7.26 (m,4H), 7.27-7.36 (m, 2H), 7.39-7.48 (m, 2H), 7.53 (dd, J=15.7, 7.8, 2H),7.61-7.75 (m, 2H), 12.39 (s, 1H)

Example 62-cyclopropyl-4-(4-fluorobenzyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.89 g), sodium hydrogencarbonate (1.4 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[2-cyclopropyl-4-(4-fluorobenzyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.44 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.17 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.2 g,58%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84-0.96 (m, 5H), 0.96-1.08 (m, 2H),1.43-1.67 (m, 2H), 2.01-2.14 (m, 1H), 2.82-2.95 (m, 2H), 3.94 (s, 2H),5.20 (s, 2H), 7.11-7.25 (m, 4H), 7.26-7.33 (m, 2H), 7.39-7.47 (m, 2H),7.47-7.59 (m, 2H), 7.61-7.75 (m, 2H), 12.39 (s, 1H)

Example 74-[(6-ethylpyridin-3-yl)methyl]-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.9 g), sodium hydrogencarbonate (1.4 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-({4-[(6-ethylpyridin-3-yl)methyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.43 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.17 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.22 g,46%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3, 3H), 1.17 (t, J=7.2, 3H),1.48-1.62 (m, 2H), 2.36 (s, 3H), 2.70 (q, J=7.5, 2H), 2.84-2.95 (m, 2H),3.96 (s, 2H), 5.26 (s, 2H), 7.18-7.25 (m, 3H), 7.27-7.34 (m, 2H),7.47-7.59 (m, 2H), 7.62-7.73 (m, 3H), 8.54 (d, J=2.1, 1H), 12.39 (br.s., 1H)

Example 84-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.49 g), sodium hydrogencarbonate (2.4 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-[(4-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.52 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.28 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.24 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.24 g,38%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.88-0.96 (m, 3H), 1.48-1.63 (m, 2H),2.89-3.00 (m, 2H), 3.55 (s, 3H), 3.97 (s, 2H), 7.18-7.24 (m, 2H),7.28-7.34 (m, 2H), 7.47-7.58 (m, 2H), 7.62-7.74 (m, 2H), 8.18 (s, 1H),12.39 (s, 1H)

Example 94-(2,2-dimethylpropyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.95 g), sodium hydrogencarbonate (1.53 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[4-(2,2-dimethylpropyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.4 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.18 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.18 g,40%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.88-1.01 (m, 12H) 1.46-1.63 (m, 2H)2.90-3.02 (m, 2H) 3.98 (s, 2H) 4.01-4.08 (m, 2H) 7.16-7.25 (m, 2H)7.27-7.35 (m, 2H) 7.52 (dd, J=17.4, 7.6 Hz, 2H) 7.59-7.70 (m, 2H) 8.15(s, 1H) 12.38 (br. s., 1H)

Example 104-(3,3-dimethyl-2-oxobutyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.9 g), sodium hydrogencarbonate (1.4 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[4-(3,3-dimethyl-2-oxobutyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.4 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.17 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.17 g,37%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.3 Hz, 3H) 1.23 (s, 9H)1.48-1.68 (m, 2H) 2.95-3.05 (m, 2H) 3.98 (s, 2H) 5.20 (s, 2H) 7.19-7.27(m, 2H) 7.27-7.35 (m, 2H) 7.46-7.59 (m, 2H) 7.61-7.73 (m, 2H) 8.17 (s,1H) 12.38 (br. s., 1H)

Example 114-[2-(4-fluorophenyl)-2-hydroxyethyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.94 g), sodium hydrogencarbonate (1.51 g) and dimethyl sulfoxide (10 mL) was stirred at 50° C.for 30 min,4′-({4-[2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-fluorophenyl)ethyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.56 g) was added, and the mixture was stirred at 90° C. for 20 hr.After allowing to cool to room temperature, ethyl acetate and water wereadded to the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with water and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography, and dissolved in tetrahydrofuran (10mL). N,N′-Carbonyldiimidazole (0.18 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 mL) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 1 N hydrochloric acid and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). Tetrabutylammonium fluoride (1 Mtetrahydrofuran solution, 2.7 mL) was added, and the mixture was stirredat room temperature for 3 hr. The reaction mixture was extracted withethyl acetate and 1 N hydrochloric acid, and the organic layer waswashed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.31 g, 61%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91 (t, J=7.3, 3H), 1.46-1.62 (m, 2H),2.89-3.00 (m, 2H), 3.96 (s, 2H), 4.15 (dd, J=13.0, 4.9, 1H), 4.37 (dd,J=13.0, 8.7, 1H), 5.11-5.21 (m, 1H), 5.66 (d, J=4.5, 1H), 7.09-7.28 (m,6H), 7.32-7.41 (m, 2H), 7.46-7.58 (m, 2H), 7.62-7.72 (m, 2H), 8.18 (s,1H), 12.40 (s, 1H)

Example 124-[2-(4-fluorophenyl)-2-oxoethyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4-[2-(4-fluorophenyl)-2-hydroxyethyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.31 g), Dess-Martin reagent (0.35 g) and acetonitrile (10 mL) wasstirred at room temperature for 2 hr. Saturated aqueous sodium hydrogencarbonate solution and sodium thiosulfate were added to the reactionmixture, and the mixture was stirred at room temperature for 2 hr, andextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography to give the title compound as acolorless amorphous solid (0.2 g, 65%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.96 (t, J=7.3, 3H), 1.54-1.67 (m, 2H),2.97-3.08 (m, 2H), 4.00 (s, 2H), 5.71 (s, 2H), 7.20-7.27 (m, 2H),7.28-7.35 (m, 2H), 7.40-7.59 (m, 4H), 7.62-7.72 (m, 2H), 8.16-8.25 (m,3H), 12.39 (s, 1H)

Example 13 tert-butyl[5-oxo-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl]acetate

A mixture of hydroxylammonium chloride (1.7 g), sodium hydrogencarbonate (2.7 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min, tert-butyl{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}acetate(0.8 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.32 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.27 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.73 g,82%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H), 1.39 (s, 9H),1.49-1.61 (m, 2H), 2.94-3.05 (m, 2H), 3.99 (s, 2H), 4.78 (s, 2H),7.19-7.26 (m, 2H), 7.27-7.33 (m, 2H), 7.47-7.59 (m, 2H), 7.62-7.72 (m,2H), 8.21 (s, 1H), 12.38 (s, 1H)

Example 144-(2-hydroxyethyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.6 g), sodium hydrogencarbonate (2.6 g) and dimethyl sulfoxide (15 mL) was stirred at 50° C.for 30 min,4′-{[4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.82 g) was added, and the mixture was stirred at 90° C. for 20 hr.After allowing to cool to room temperature, ethyl acetate and water wereadded to the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with water and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography, and dissolved in tetrahydrofuran (15mL). N,N′-Carbonyldiimidazole (0.3 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 mL) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 1 N hydrochloric acid and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). Tetrabutylammonium fluoride (1 Mtetrahydrofuran solution, 2.7 mL) was added, and the mixture was stirredat room temperature for 3 hr. The reaction mixture was extracted withethyl acetate and 1 N hydrochloric acid, and the organic layer waswashed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.31 g, 61%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3, 3H), 1.45-1.65 (m, 2H),2.88-3.00 (m, 2H), 3.66-3.76 (m, 2H), 3.98 (s, 2H), 4.18-4.26 (m, 2H),4.86 (t, J=6.0, 1H), 7.19-7.26 (m, 2H), 7.29-7.35 (m, 2H), 7.47-7.58 (m,2H), 7.61-7.72 (m, 2H), 8.17 (s, 1H), 12.39 (br. s., 1H)

Example 152-[5-oxo-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl]acetamide

A mixture of hydroxylammonium chloride (1.3 g), sodium hydrogencarbonate (2.1 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,2-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}acetamide(0.48 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.24 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.25 g,42%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.3, 3H), 1.47-1.65 (m, 2H),2.91-3.03 (m, 2H), 3.98 (s, 2H), 4.67 (s, 2H), 7.20-7.36 (m, 5H),7.48-7.59 (m, 2H), 7.61-7.76 (m, 3H), 8.17 (s, 1H), 12.39 (br. s., 1H)

Example 16[5-oxo-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl]aceticacid

A mixture of tert-butyl[5-oxo-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl]acetate(0.58 g) and trifluoroacetic acid (10 mL) was stirred at roomtemperature for 2 hr. The reaction mixture was diluted with toluene (10mL), and the solvent was evaporated under reduced pressure. The residuewas purified by silica gel column chromatography to give the titlecompound as a colorless solid (0.19 g, 36%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.3, 3H), 1.46-1.67 (m, 2H),2.91-3.06 (m, 2H), 3.99 (s, 2H), 4.81 (s, 2H), 7.20-7.25 (m, 2H),7.28-7.35 (m, 2H), 7.47-7.58 (m, 2H), 7.62-7.73 (m, 2H), 8.21 (s, 1H),12.15-13.63 (m, 2H)

Example 174-(1-methylethyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.2 g), sodium hydrogencarbonate (1.9 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[4-(1-methylethyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.48 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.22 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.19 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.19 g,35%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3, 3H), 1.47-1.61 (m, 8H),2.88-2.97 (m, 2H), 3.96 (s, 2H), 5.22-5.35 (m, 1H), 7.19-7.27 (m, 2H),7.28-7.34 (m, 2H), 7.48-7.58 (m, 2H), 7.61-7.72 (m, 2H), 8.19 (s, 1H),12.38 (s, 1H)

Example 184-(2-hydroxy-2-methylpropyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.8 g), sodium hydrogencarbonate (2.9 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[4-(2-hydroxy-2-methylpropyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.76 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.33 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.28 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.2 g,24%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3, 3H), 1.13 (s, 6H), 1.50-1.66(m, 2H), 2.90-2.99 (m, 2H), 3.99 (s, 2H), 4.18 (s, 2H), 4.63 (s, 1H),7.19-7.25 (m, 2H), 7.29-7.35 (m, 2H), 7.47-7.59 (m, 2H), 7.61-7.72 (m,2H), 8.16 (s, 1H), 12.38 (s, 1H)

Example 194-[(1-methyl-1H-benzimidazol-2-yl)methyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onehydrochloride

A mixture of hydroxylammonium chloride (1.7 g), sodium hydrogencarbonate (2.8 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-({4-[(1-methyl-1H-benzimidazol-2-yl)methyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.84 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.32 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.27 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography, and dissolved in ethyl acetate (10 mL), hydrochloricacid (4N ethyl acetate solution, 0.051 mL) was added, and the mixturewas stirred at room temperature. The precipitated solid was collected byfiltration to give the title compound as a colorless amorphous solid(0.13 g, 39%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.96 (t, J=7.4 Hz, 3H), 1.52-1.69 (m, 2H),2.94-3.05 (m, 2H), 4.00 (s, 2H), 4.07 (s, 3H), 5.84 (s, 2H), 7.18-7.26(m, 2H), 7.30-7.37 (m, 2H), 7.43-7.60 (m, 4H), 7.63-7.76 (m, 3H), 7.89(d, J=8.0 Hz, 1H), 8.25 (s, 1H), 12.47 (s, 1H)

Example 204-ethyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.4 g), sodium hydrogencarbonate (2.3 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-[(4-ethyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.54 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.26 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.22 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.21 g,34%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.2 Hz, 3H), 1.27 (t, J=7.0 Hz,3H), 1.45-1.64 (m, 2H), 2.88-3.01 (m, 2H), 3.98 (s, 2H), 4.16 (q, J=6.8Hz, 2H), 7.18-7.27 (m, 2H), 7.28-7.38 (m, 2H), 7.53 (dd, J=16.1, 7.8 Hz,2H), 7.61-7.77 (m, 2H), 8.20 (s, 1H), 12.39 (br. s., 1H)

Example 214-(cyclopropylmethyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.3 g), sodium hydrogencarbonate (2.2 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[4-(cyclopropylmethyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.54 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.25 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.21 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.17 g,27%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.40-0.54 (m, 4H), 0.93 (t, J=7.2 Hz, 3H),1.25-1.41 (m, 1H), 1.46-1.65 (m, 2H), 2.92-3.02 (m, 2H), 3.95-4.07 (m,4H), 7.20-7.27 (m, 2H), 7.29-7.37 (m, 2H), 7.53 (dd, J=15.9, 7.6 Hz,2H), 7.63-7.75 (m, 2H), 8.19 (s, 1H), 12.39 (s, 1H)

Example 222-methyl-4-(1-methylethyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.68 g), sodium hydrogencarbonate (1.1 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[2-methyl-4-(1-methylethyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.28 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.13 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.18 g,56%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.4 Hz, 3H) 1.42-1.61 (m, 8H)2.36 (s, 3H) 2.83-2.96 (m, 2H) 3.94 (s, 2H) 5.16-5.33 (m, 1H) 7.18-7.26(m, 2H) 7.26-7.33 (m, 2H) 7.45-7.59 (m, 2H) 7.61-7.71 (m, 2H) 12.38 (br.s., 1H)

Example 234-(2-hydroxybutyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.1 g), sodium hydrogencarbonate (1.7 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[4-(2-hydroxybutyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.28 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.17 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.28 g,54%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.85-0.98 (m, 6H), 1.29-1.64 (m, 4H),2.88-2.98 (m, 2H), 3.85-4.00 (m, 4H), 4.14-4.26 (m, 1H), 4.78 (d, J=5.3Hz, 1H), 7.18-7.25 (m, 2H), 7.26-7.36 (m, 2H), 7.53 (dd, J=16.3, 7.6 Hz,2H), 7.61-7.75 (m, 2H), 8.16 (s, 1H), 12.38 (s, 1H)

Example 242-cyclopropyl-4-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.65 g), sodium hydrogencarbonate (0.99 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-[(2-cyclopropyl-4-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.2 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.091 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.077 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.16 g,71%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.88-1.04 (m, 7H), 1.45-1.65 (m, 2H),2.01-2.14 (m, 1H), 2.84-2.95 (m, 2H), 3.48 (s, 3H), 3.94 (s, 2H),7.17-7.25 (m, 2H), 7.25-7.33 (m, 2H), 7.52 (dd, J=16.7, 7.6 Hz, 2H),7.61-7.72 (m, 2H), 12.38 (br. s., 1H)

Example 254-[4-(1-methylethoxy)phenyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.2 g), sodium hydrogencarbonate (1.9 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-({4-[4-(1-methylethoxy)phenyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.57 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.22 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.18 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.39 g,61%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.96 (t, J=7.0 Hz, 3H), 1.31 (dd, J=6.1, 1.5Hz, 6H), 1.49-1.68 (m, 2H), 2.89-3.05 (m, 2H), 3.99 (s, 2H), 4.57-4.76(m, 1H), 7.03 (d, J=7.2 Hz, 2H), 7.23 (d, J=6.8 Hz, 2H), 7.36 (d, J=8.7Hz, 4H), 7.48-7.60 (m, 2H), 7.61-7.73 (m, 2H), 8.06 (d, J=1.9 Hz, 1H),12.4 (br. s., 1H)

Example 264-[4-(1-methylethoxy)phenyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

4-[4-(1-Methylethoxy)phenyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.39 g) was suspended in water (3 mL), 2N potassium hydroxide solution(0.34 mL) was added, and the solvent was evaporated under reducedpressure. The residue was solidified with diisopropyl ether to give thetitle compound as a colorless solid (0.42 g, 100%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.96-1.06 (m, 3H), 1.30 (s, 3H), 1.32 (s,3H), 1.59-1.73 (m, 2H), 2.96-3.06 (m, 2H), 3.95 (s, 2H), 4.60-4.75 (m,1H), 7.03 (d, J=8.7 Hz, 2H), 7.19-7.50 (m, 10H), 8.04 (s, 1H)

Example 274-[4-(1-hydroxyethyl)benzyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (2.4 g), sodium hydrogencarbonate (3.9 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-({4-[4-(1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)benzyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(1.4 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.45 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.38 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was dissolved in tetrahydrofuran (30mL). Tetrabutylammonium bromide (1.0 M tetrahydrofuran solution, 5.8 mL)was added, and the mixture was stirred at 50° C. for 3 hr. The reactionmixture was extracted with 1 N hydrochloric acid and ethyl acetate, andthe ethyl acetate layer was washed with saturated brine andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.72 g,56%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H), 1.27 (d, J=6.4 Hz,3H), 1.49-1.63 (m, 2H), 2.89-3.02 (m, 2H), 3.99 (s, 2H), 4.60-4.74 (m,1H), 5.09 (d, J=4.1 Hz, 1H), 5.28 (s, 2H), 7.18-7.36 (m, 8H), 7.46-7.59(m, 2H), 7.62-7.73 (m, 2H), 8.20 (s, 1H), 12.39 (s, 1H)

Example 284-(4-acetylbenzyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4-[4-(1-hydroxyethyl)benzyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.5 g), manganese dioxide (2.3 g) and methylene chloride (20 mL) wasstirred at room temperature for 16 hr. The insoluble material wasfiltered off through celite, and the filtrate was concentrated. Theobtained residue was purified by silica gel column chromatography togive the title compound as colorless crystals (0.43 g, 85%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H), 1.49-1.65 (m, 2H),2.54 (s, 3H), 2.90-3.03 (m, 2H), 3.99 (s, 2H), 5.37 (s, 2H), 7.18-7.26(m, 2H), 7.28-7.36 (m, 2H), 7.44-7.59 (m, 4H), 7.62-7.71 (m, 2H),7.87-7.96 (m, 2H), 8.19 (s, 1H), 12.39 (s, 1H)

Example 296-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4,7-dipropyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.3 g), sodium hydrogencarbonate (2.1 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-[(5-oxo-4,7-dipropyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.5 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.24 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.26 g,45%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91 (q, J=7.6 Hz, 6H), 1.45-1.63 (m, 2H),1.63-1.81 (m, 2H), 2.88-3.02 (m, 2H), 3.97 (s, 2H), 4.05-4.15 (m, 2H),7.19-7.25 (m, 2H), 7.27-7.36 (m, 2H), 7.53 (dd, J=16.5, 7.8 Hz, 2H),7.60-7.73 (m, 2H), 8.18 (s, 1H), 12.36 (s, 1H)

Example 306-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-phenyl-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.4 g), sodium hydrogencarbonate (2.2 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-[(5-oxo-4-phenyl-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.58 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.25 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.21 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.23 g,44%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.97 (t, J=7.4 Hz, 3H), 1.50-1.70 (m, 2H),2.91-3.05 (m, 2H), 4.01 (s, 2H), 7.23 (d, J=8.0 Hz, 2H), 7.37 (d, J=8.3Hz, 2H), 7.42-7.60 (m, 7H), 7.61-7.74 (m, 2H), 8.06 (s, 1H), 12.38 (s,1H)

Example 312-methyl-4-[4-(1-methylethoxy)phenyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.81 g), sodium hydrogencarbonate (1.3 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-({2-methyl-4-[4-(1-methylethoxy)phenyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.4 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.15 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.13 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.24 g,53%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.96 (t, J=7.3 Hz, 3H), 1.31 (d, J=6.0 Hz,6H), 1.50-1.69 (m, 2H), 2.26 (s, 3H), 2.94 (dd, J=9.0, 6.4 Hz, 2H), 3.97(s, 2H), 4.58-4.74 (m, 1H), 6.96-7.09 (m, 2H), 7.17-7.26 (m, 2H),7.29-7.40 (m, 4H), 7.46-7.58 (m, 2H), 7.61-7.77 (m, 2H), 12.39 (s, 1H)

Example 322-methyl-4-[4-(1-methylethoxy)phenyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

2-Methyl-4-[4-(1-methylethoxy)phenyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.24 g) was suspended in isopropyl alcohol (5 mL), 2N potassiumhydroxide solution (0.21 mL) was added, and the solvent was evaporatedunder reduced pressure. The residue was solidified with diisopropylether to give the title compound as a colorless solid (0.23 g, 95%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.99 (t, J=7.4 Hz, 3H), 1.31 (d, J=6.1 Hz,6H), 1.58-1.72 (m, 2H), 2.25 (s, 3H), 2.89-3.01 (m, 2H), 3.92 (s, 2H),4.60-4.74 (m, 1H), 7.02 (d, J=8.7 Hz, 2H), 7.22 (s, 4H), 7.25-7.53 (m,6H)

Example 334-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.7 g), sodium hydrogencarbonate (2.8 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[4-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.86 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.32 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.27 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.44 g,46%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.96 (t, J=7.3 Hz, 3H), 1.46 (s, 6H),1.53-1.67 (m, 2H), 2.93-3.02 (m, 2H), 3.06 (s, 2H), 3.99 (s, 2H), 6.81(d, J=8.5 Hz, 1H), 7.15 (dd, J=8.5, 2.3 Hz, 1H), 7.21-7.27 (m, 3H),7.32-7.39 (m, 2H), 7.46-7.58 (m, 2H), 7.62-7.75 (m, 2H), 8.06 (s, 1H),12.39 (s, 1H)

Example 344-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

4-(2,2-Dimethyl-2,3-dihydro-1-benzofuran-5-yl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.44 g) was suspended in isopropyl alcohol (5 mL), 2N potassiumhydroxide solution (0.39 mL) was added, and the solvent was evaporatedunder reduced pressure. The residue was solidified with diisopropylether to give the title compound as a colorless solid (0.45 g, 95%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95-1.03 (m, 3H) 1.46 (s, 6H) 1.59-1.72 (m,2H) 2.95-3.11 (m, 4H) 3.94 (s, 2H) 6.80 (d, J=8.3 Hz, 1H) 7.12-7.51 (m,10H) 8.03 (s, 1H)

Example 356-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-phenyl-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

6-{[2′-(5-Oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-phenyl-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.21 g) was suspended in isopropyl alcohol (5 mL), 2N potassiumhydroxide solution (0.2 mL) was added, and the solvent was evaporatedunder reduced pressure. The residue was solidified with diisopropylether to give the title compound as a colorless solid (0.2 g, 89%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.97 (t, J=7.4 Hz, 3H), 1.50-1.70 (m, 2H),2.91-3.05 (m, 2H), 4.01 (s, 2H), 7.23 (d, J=8.0 Hz, 2H), 7.37 (d, J=8.3Hz, 2H), 7.42-7.60 (m, 7H), 7.61-7.74 (m, 2H), 8.06 (s, 1H), 12.38 (s,1H)

Example 364-ethyl-6-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of3′-fluoro-4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(1 g), iodoethane (0.25 mL), potassium carbonate (0.71 g) andN,N-dimethylformamide (10 mL) was stirred at room temperature for 3 hr.The reaction mixture was diluted with ethyl acetate, washed with 5%aqueous potassium hydrogensulfate solution and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The residue obtained by silica gelcolumn chromatography was dissolved in dimethyl sulfoxide (5 mL), andthe mixture was added to a mixture of hydroxylammonium chloride (0.4 g),sodium hydrogen carbonate (0.65 g) and dimethyl sulfoxide (5 mL), whichhad been stirred in advance at 40° C. for 30 min. The reaction mixturewas stirred at 90° C. for 16 hr, and diluted with ethyl acetate, and themixture was washed with water and then with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was dissolved in tetrahydrofuran (10mL). N,N′-Carbonyldiimidazole (0.075 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.063 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.1 g,8%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H), 1.25 (t, J=7.1 Hz,3H), 1.51-1.67 (m, 2H), 2.87-3.00 (m, 2H), 3.96 (s, 2H), 4.14 (q, J=6.9Hz, 2H), 6.99 (dd, J=7.9, 1.7 Hz, 1H), 7.17 (dd, J=11.2, 1.8 Hz, 1H),7.24 (t, J=8.1 Hz, 1H), 7.50-7.63 (m, 2H), 7.63-7.76 (m, 2H), 8.20 (s,1H), 12.46 (s, 1H)

Example 374-(2,4-dimethoxybenzyl)-6-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.7 g), sodium hydrogencarbonate (1.1 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[4-(2,4-dimethoxybenzyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile(0.36 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.13 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.18 g, 45%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.3 Hz, 3H), 1.51-1.70 (m, 2H),2.91-3.04 (m, 2H), 3.71 (s, 3H), 3.77 (s, 3H), 3.98 (s, 2H), 5.19 (s,2H), 6.39 (dd, J=8.5, 2.4 Hz, 1H), 6.56 (d, J=2.3 Hz, 1H), 6.75 (d,J=8.5 Hz, 1H), 7.00 (dd, J=8.0, 1.8 Hz, 1H), 7.18 (dd, J=11.1, 1.7 Hz,1H), 7.26 (t, J=8.0 Hz, 1H), 7.47-7.62 (m, 2H), 7.63-7.76 (m, 2H), 8.15(s, 1H), 12.47 (s, 1H)

Example 386-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4-(2,4-dimethoxybenzyl)-6-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.3 g), trifluoroacetic acid (5 mL) and toluene (5 mL) was stirred atroom temperature for 16 hr. The reaction mixture was concentrated, andthe residue was purified by silica gel column chromatography to give thetitle compound as a colorless amorphous solid (0.022 g, 10%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H), 1.47-1.67 (m, 2H),2.83-2.99 (m, 2H), 3.91 (s, 2H), 7.00 (dd, J=7.8, 1.4 Hz, 1H), 7.16 (dd,J=11.1, 1.3 Hz, 1H), 7.24 (t, J=7.9 Hz, 1H), 7.46-7.63 (m, 2H),7.64-7.75 (m, 2H), 8.11 (s, 1H), 12.46 (br. s., 1H), 13.11 (br. s., 1H)

Example 394-(4-methoxyphenyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.4 g), sodium hydrogencarbonate (2.3 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[4-(4-methoxyphenyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.64 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.26 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.22 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.45 g,63%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.96 (t, J=7.4 Hz, 3H), 1.51-1.69 (m, 2H),2.91-3.06 (m, 2H), 3.82 (s, 3H), 4.00 (s, 2H), 7.01-7.10 (m, 2H), 7.23(d, J=8.3 Hz, 2H), 7.33-7.42 (m, 4H), 7.47-7.58 (m, 2H), 7.62-7.73 (m,2H), 8.06 (s, 1H), 12.38 (s, 1H)

Example 406-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-phenyl-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.4 g), sodium hydrogencarbonate (2.2 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,3′-fluoro-4′-[(5-oxo-4-phenyl-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.61 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.25 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.22 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.34 g,48%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.98 (t, J=7.4 Hz, 3H), 1.56-1.73 (m, 2H),2.94-3.05 (m, 2H), 3.99 (s, 2H), 7.01 (dd, J=8.0, 1.9 Hz, 1H), 7.17 (dd,J=11.2, 1.7 Hz, 1H), 7.36 (t, J=8.1 Hz, 1H), 7.42-7.75 (m, 9H), 8.08 (s,1H), 12.45 (s, 1H)

Example 416-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-phenyl-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

6-{[3-Fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-phenyl-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.34 g) was suspended in isopropyl alcohol (5 mL), 2N potassiumhydroxide solution (0.32 mL) was added, and the solvent was evaporatedunder reduced pressure. The residue was solidified with diisopropylether to give the title compound as a colorless solid (0.35 g, 97%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.96-1.03 (m, 3H), 1.58-1.76 (m, 2H),2.96-3.06 (m, 2H), 3.95 (s, 2H), 6.99-7.14 (m, 2 H), 7.19-7.57 (m, 10H),8.06 (s, 1H)

Example 426-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.93 g), sodium hydrogencarbonate (1.5 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[4-(methoxymethyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile(0.38 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (15 mL). Thiocarbonyldiimidazole (0.19 g)was added, and the mixture was stirred at room temperature for 1 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (15 mL), boron trifluoride-diethyl ethercomplex (0.56 mL) was added at 0° C., and the mixture was stirred for 1hr. The reaction mixture was diluted with ethyl acetate, washed withsaturated aqueous potassium hydrogensulfate solution and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The residue obtained bypurification by silica gel column chromatography was dissolved inmethylene chloride solution (10 mL), boron tribromide (1.0 M methylenechloride solution, 1.1 mL) was added, and the mixture was stirred atroom temperature for 1 day. The reaction mixture was extracted withethyl acetate and water. The organic layer was washed with saturatedbrine, and dried over anhydrous magnesium sulfate, and the solvent wasevaporated. The residue was purified by silica gel column chromatographyto give the title compound as colorless crystals (0.029 g, 7%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91 (t, J=7.2 Hz, 3H), 1.46-1.66 (m, 2H),2.82-2.95 (m, 2H), 3.89 (s, 2H), 6.93 (dd, J=8.0, 1.5 Hz, 1H), 7.02-7.12(m, 1H), 7.21 (t, J=8.1 Hz, 1H), 7.53 (t, J=7.8 Hz, 2H), 7.58-7.69 (m,2H), 8.11 (s, 1H), 12.93 (s, 1H), 13.10 (br. s., 1H)

Example 436-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[4-(1-methylethoxy)phenyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.2 g), sodium hydrogencarbonate (1.9 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,3′-fluoro-4′-({4-[4-(1-methylethoxy)phenyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.59 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.22 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.19 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.42 g,64%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.97 (t, J=7.3 Hz, 3H), 1.30 (d, J=6.0 Hz,6H), 1.55-1.72 (m, 2H), 2.94-3.04 (m, 2H), 3.98 (s, 2H), 4.60-4.76 (m,1H), 6.96-7.08 (m, 3H), 7.17 (dd, J=11.1, 1.7 Hz, 1H), 7.29-7.39 (m,3H), 7.49-7.61 (m, 2H), 7.65-7.75 (m, 2H), 8.04-8.10 (m, 1H), 12.46 (br.s., 1H)

Example 444-(4-methoxyphenyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

4-(4-Methoxyphenyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.3 g) was suspended in isopropyl alcohol (5 mL), 2N potassiumhydroxide solution (0.28 mL) was added, and the solvent was evaporatedunder reduced pressure. The residue was solidified with diisopropylether to give the title compound as a colorless solid (0.3 g, 94%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95-1.03 (m, 3H), 1.58-1.73 (m, 2H),2.95-3.06 (m, 2H), 3.82 (s, 3H), 3.95 (s, 2H), 7.03-7.10 (m, 2H),7.19-7.50 (m, 10H), 8.04 (s, 1H)

Example 456-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[4-(1-methylethoxy)phenyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

6-{[3-Fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[4-(1-methylethoxy)phenyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.36 g) was suspended in isopropyl alcohol (10 mL), 2N potassiumhydroxide solution (0.31 mL) was added, and the solvent was evaporatedunder reduced pressure. The residue was solidified with diisopropylether to give the title compound as a colorless solid (0.35 g, 92%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95-1.02 (m, 3H), 1.27-1.34 (m, 6H),1.62-1.74 (m, 2H), 2.95-3.06 (m, 2H), 3.94 (s, 2H), 4.59-4.75 (m, 1H),6.97-7.13 (m, 4H), 7.23 (t, J=8.1 Hz, 1H), 7.27-7.46 (m, 5H), 7.48-7.53(m, 1H), 8.06 (s, 1H)

Example 467-butyl-4-[4-(1-methylethoxy)phenyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.4 g), sodium hydrogencarbonate (2.2 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-({4-[4-(1-methylethoxy)phenyl]-5-oxo-7-butyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.69 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.26 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.22 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.31 g,40%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.79-0.92 (m, 3H), 1.31 (d, J=6.0 Hz, 6H),1.35-1.46 (m, 2H), 1.47-1.62 (m, 2H), 2.93-3.04 (m, 2H), 3.99 (s, 2H),4.61-4.76 (m, 1H), 6.99-7.06 (m, 2H), 7.18-7.28 (m, 2H), 7.32-7.40 (m,4H), 7.45-7.58 (m, 2H), 7.62-7.72 (m, 2H), 8.06 (s, 1H), 12.40 (s, 1H)

Example 477-butyl-4-[4-(1-methylethoxy)phenyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

7-Butyl-4-[4-(1-methylethoxy)phenyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.069 g) was suspended in isopropyl alcohol (15 mL), 2N potassiumhydroxide solution (0.066 mL) was added, and the solvent was evaporatedunder reduced pressure. The residue was solidified with diisopropylether to give the title compound as a colorless solid (0.051 g, 63%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.88 (t, J=7.2 Hz, 3H), 1.31 (d, J=6.1 Hz,6H), 1.37-1.46 (m, 2H), 1.51-1.63 (m, 2H), 2.95-3.08 (m, 2H), 3.94 (s,2H), 4.63-4.74 (m, 1H), 6.97-7.08 (m, 2H), 7.18-7.51 (m, 10H), 8.03 (s,1H)

Example 487-butyl-6-{[3,5-difluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.87 g), sodium hydrogencarbonate (1.4 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[7-butyl-4-(methoxymethyl)-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′,5′-difluorobiphenyl-2-carbonitrile(0.39 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.16 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The residue obtained by purification by silica gelcolumn chromatography was dissolved in methylene chloride solution (10mL), boron tribromide (1.0 M methylene chloride solution, 2.2 mL) wasadded, and the mixture was stirred at room temperature for 1 day. Ethylacetate and water were added to the reaction mixture, and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate, and thesolvent was evaporated. The residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.029g, 7%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.81-0.90 (m, 3H), 1.30-1.52 (m, 4H),2.90-3.02 (m, 2H), 3.94 (s, 2H), 7.01 (d, J=8.7 Hz, 2H), 7.48-7.75 (m,4H), 8.11 (s, 1H), 12.55 (br. s., 1H), 13.08 (br. s., 1H)

Example 497-butyl-4-(3-fluoro-4-methoxyphenyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.6 g), sodium hydrogencarbonate (2.6 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-({7-butyl-4-[3-fluoro-4-methoxyphenyl]-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.78 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.3 g)and then with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 mL) were added,and the mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.46 g,53%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.82-0.90 (m, 3H) 1.31-1.46 (m, 2H)1.45-1.58 (m, 2H) 2.94-3.05 (m, 2H) 3.91 (s, 3H) 3.99 (s, 2H) 7.23 (d,J=8.3 Hz, 2H) 7.28-7.39 (m, 4H) 7.45-7.57 (m, 3H) 7.63-7.73 (m, 2H) 8.08(s, 1H) 12.40 (s, 1H)

Example 507-butyl-4-(3-fluoro-4-methoxyphenyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

7-Butyl-4-(3-fluoro-4-methoxyphenyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.46 g) was suspended in isopropyl alcohol (15 mL), 2N potassiumhydroxide solution (0.41 mL) was added, and the solvent was evaporatedunder reduced pressure. The residue was solidified with diisopropylether to give the title compound as a colorless solid (0.45 g, 90%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84-0.93 (m, 3H) 1.33-1.49 (m, 2H)1.50-1.64 (m, 2H) 2.95-3.07 (m, 2H) 3.91 (s, 3H) 3.95 (s, 2H) 7.23 (s,4H) 7.25-7.53 (m, 7H) 8.06 (s, 1H)

Example 517-butyl-4-[3-fluoro-4-(1-methylethoxy)phenyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.3 g), sodium hydrogencarbonate (2.1 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-({7-butyl-4-[3-fluoro-4-(1-methylethoxy)phenyl]-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.68 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.25 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.21 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.37 g,49%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.82-0.91 (m, 3H), 1.31-1.44 (m, 8H),1.46-1.60 (m, 2H), 2.94-3.06 (m, 2H), 3.99 (s, 2H), 4.64-4.79 (m, 1H),7.21-7.40 (m, 6H), 7.40-7.59 (m, 3H), 7.61-7.74 (m, 2H), 8.08 (s, 1H),12.39 (s, 1H)

Example 527-butyl-4-[3-fluoro-4-(1-methylethoxy)phenyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

7-Butyl-4-[3-fluoro-4-(1-methylethoxy)phenyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.37 g) was suspended in isopropyl alcohol (15 mL), 2N potassiumhydroxide solution (0.31 mL) was added, and the solvent was evaporatedunder reduced pressure. The residue was solidified with diisopropylether to give the title compound as a colorless solid (0.33 g, 84%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.88 (t, J=7.3 Hz, 3H), 1.33 (d, J=6.0 Hz,6H), 1.36-1.49 (m, 2H), 1.49-1.64 (m, 2H), 2.95-3.06 (m, 2H), 3.94 (s,2H), 4.65-4.78 (m, 1H), 7.19-7.50 (m, 11H), 8.06 (s, 1H)

Example 537-butyl-6-{[3,5-difluoro-2′-(5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.89 g), sodium hydrogencarbonate (1.4 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[7-butyl-4-(methoxymethyl)-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′,5′-difluorobiphenyl-2-carbonitrile(0.39 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (15 mL). Thiocarbonyldiimidazole (0.18 g)was added, and the mixture was stirred at room temperature for 1 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (15 mL), boron trifluoride-diethyl ethercomplex (0.52 mL) was added at 0° C., and the mixture was stirred for 1hr. The reaction mixture was diluted with ethyl acetate, washed withsaturated aqueous potassium hydrogensulfate solution and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The residue obtained bypurification by silica gel column chromatography was dissolved inmethylene chloride solution (10 mL), boron tribromide (1.0 M methylenechloride solution, 0.56 mL) was added, and the mixture was stirred atroom temperature for 1 day. Ethyl acetate and water were added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate, and the solvent was evaporated. The residue waspurified by silica gel column chromatography to give the title compoundas colorless crystals (0.035 g, 9%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.81-0.89 (m, 3H), 1.27-1.51 (m, 4H),2.89-3.01 (m, 2H), 3.93 (s, 2H), 6.86-6.97 (m, 2H), 7.49-7.60 (m, 2H),7.60-7.69 (m, 2H), 8.10 (s, 1H), 13.01 (s, 1H), 13.07 (s, 1H)

Example 544-[4-(1-methylethyl)phenyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.3 g), sodium hydrogencarbonate (2.2 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-({4-[4-(1-methylethyl)phenyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.63 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.25 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.21 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.29 g,42%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.97 (t, J=7.3 Hz, 3H), 1.26 (d, J=6.8 Hz,6H), 1.52-1.68 (m, 2H), 2.93-3.05 (m, 3H), 4.00 (s, 2H), 7.23 (d, J=8.3Hz, 2H), 7.32-7.44 (m, 6H), 7.48-7.58 (m, 2H), 7.62-7.73 (m, 2H), 8.06(s, 1H), 12.39 (s, 1H)

Example 554-[4-(1-methylethyl)phenyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

4-[4-(1-Methylethyl)phenyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.24 g) was suspended in isopropyl alcohol (10 mL), 2N potassiumhydroxide solution (0.22 mL) was added, and the solvent was evaporatedunder reduced pressure. The residue was solidified with diisopropylether to give the title compound as a colorless solid (0.26 g, 100%).

¹H NMR (300 MHz, DMSO-d₆) δ 1.00 (t, J=7.5 Hz, 3H), 1.25 (s, 3H), 1.27(s, 3H), 1.58-1.73 (m, 2H), 2.91-3.08 (m, 3H), 3.95 (s, 2H), 7.17-7.49(m, 12H), 8.04 (s, 1H)

Example 564-[4-(1-hydroxy-1-methylethyl)phenyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.97 g), sodium hydrogencarbonate (1.7 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-({4-[4-(1-hydroxy-1-methylethyl)phenyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.47 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.13 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.13 g,24%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.97 (t, J=7.3 Hz, 3H), 1.48 (s, 6H),1.55-1.68 (m, 2H), 2.93-3.06 (m, 2H), 4.00 (s, 2H), 7.23 (d, J=8.1 Hz,2H), 7.33-7.41 (m, 4H), 7.47-7.73 (m, 6H), 8.06 (s, 1H), 12.39 (s, 1H)

Example 574-(3-methoxyphenyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.4 g), sodium hydrogencarbonate (2.3 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[4-(3-methoxyphenyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.65 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.27 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.34 g,46%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.97 (t, J=7.4 Hz, 3H), 1.52-1.68 (m, 2H),2.94-3.04 (m, 2H), 3.77 (s, 3H), 4.00 (s, 2H), 7.00-7.13 (m, 3H), 7.23(d, J=8.3 Hz, 2H), 7.33-7.58 (m, 5H), 7.61-7.74 (m, 2H), 8.07 (s, 1H),12.40 (br. s., 1H)

Example 584-(3,4-dimethoxyphenyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.2 g), sodium hydrogencarbonate (1.9 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[4-(3,4-dimethoxyphenyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.58 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.22 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.19 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.41 g,63%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.96 (t, J=7.5 Hz, 3H), 1.53-1.70 (m, 2H),2.92-3.05 (m, 2H), 3.72 (s, 3H), 3.81 (s, 3H), 4.00 (s, 2H), 6.96-7.16(m, 3H), 7.24 (d, J=8.3 Hz, 2H), 7.37 (d, J=8.3 Hz, 2H), 7.47-7.59 (m,2H), 7.62-7.74 (m, 2H), 8.07 (s, 1H), 12.40 (br. s., 1H)

Example 594-[4-(1-hydroxyethyl)phenyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.83 g), sodium hydrogencarbonate (1.4 g) and dimethyl sulfoxide (10 mL) was stirred at 50° C.for 30 min,4′-({4-[4-(1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.49 g) was added, and the mixture was stirred at 90° C. for 20 hr.After allowing to cool to room temperature, the reaction mixture wasextracted with ethyl acetate and water, and the organic layer was washedwith water and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography, anddissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.16 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.13 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 N hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was dissolved in tetrahydrofuran (15 mL). Tetrabutylammoniumfluoride (1 M tetrahydrofuran solution, 2 mL) was added, and the mixturewas stirred at 50° C. for 3 hr. Ethyl acetate and water were added tothe reaction mixture, and the mixture was extracted with ethyl acetate.The organic layer was washed with water and then with saturated brine,and dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography to give the title compound as colorless crystals(0.2 g, 44%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.97 (t, J=7.3 Hz, 3H), 1.37 (d, J=6.4 Hz,3H), 1.52-1.69 (m, 2H), 2.94-3.04 (m, 2H), 4.00 (s, 2H), 4.73-4.85 (m,1H), 5.29 (d, J=4.1 Hz, 1H), 7.23 (d, J=8.3 Hz, 2H), 7.34-7.43 (m, 4H),7.46-7.59 (m, 4H), 7.63-7.72 (m, 2H), 8.06 (s, 1H), 12.39 (s, 1H)

Example 604-(4-fluorophenyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.3 g), sodium hydrogencarbonate (2.1 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[4-(4-fluorophenyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.57 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.24 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.36 g,55%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.97 (t, J=7.5 Hz, 3H), 1.52-1.70 (m, 2H),2.94-3.06 (m, 2H), 4.00 (s, 2H), 7.23 (d, J=8.3 Hz, 2H), 7.33-7.44 (m,4H), 7.46-7.60 (m, 4H), 7.62-7.75 (m, 2H), 8.08 (s, 1H), 12.39 (br. s.,1H)

Example 614-(4-fluorophenyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

4-(4-Fluorophenyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.36 g) was suspended in isopropyl alcohol (15 mL), 2N potassiumhydroxide solution (0.34 mL) was added, and the solvent was evaporatedunder reduced pressure. The residue was solidified with diisopropylether to give the title compound as a colorless solid (0.3 g, 79%).

¹H NMR (300 MHz, DMSO-d₆) δ 1.00 (t, J=7.4 Hz, 3H), 1.59-1.73 (m, 2H),2.97-3.06 (m, 2H), 3.95 (s, 2H), 7.20-7.49 (m, 10H), 7.54-7.61 (m, 2H),8.05 (s, 1H)

Example 624-(3-fluoro-4-methoxyphenyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.3 g), sodium hydrogencarbonate (2.1 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[4-(3-fluoro-4-methoxyphenyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.6 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.24 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.4 g,60%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.96 (t, J=7.3 Hz, 3H), 1.52-1.67 (m, 2H),2.90-3.04 (m, 2H), 3.91 (s, 3H), 4.01 (s, 2H), 7.23 (d, J=8.1 Hz, 2H),7.28-7.33 (m, 2H), 7.37 (d, J=8.3 Hz, 2H), 7.43-7.59 (m, 3H), 7.62-7.74(m, 2H), 8.08 (s, 1H), 12.39 (s, 1H)

Example 634-(3-fluoro-4-methoxyphenyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

4-(3-Fluoro-4-methoxyphenyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.4 g) was suspended in isopropyl alcohol (15 mL), 2N potassiumhydroxide solution (0.37 mL) was added, and the solvent was evaporatedunder reduced pressure. The residue was solidified with diisopropylether to give the title compound as a colorless solid (0.34 g, 80%).

¹H NMR (300 MHz, DMSO-d₆) δ 1.00 (t, J=7.4 Hz, 3H), 1.59-1.72 (m, 2H),2.94-3.06 (m, 2H), 3.91 (s, 3H), 3.95 (s, 2H), 7.19-7.52 (m, 11H), 8.06(s, 1H)

Example 644-(3-methoxyphenyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

4-(3-Methoxyphenyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.29 g) was suspended in isopropyl alcohol (15 mL), 2N potassiumhydroxide solution (0.27 mL) was added, and the solvent was evaporatedunder reduced pressure. The residue was solidified with diisopropylether to give the title compound as a colorless solid (0.3 g, 100%).

¹H NMR (300 MHz, DMSO-d₆) δ 1.00 (t, J=7.4 Hz, 3H), 1.57-1.73 (m, 2H),2.97-3.06 (m, 2H), 3.77 (s, 3H), 3.95 (s, 2H), 7.06 (dd, J=8.1, 3.4 Hz,2H), 7.13 (t, J=2.2 Hz, 1H), 7.20-7.48 (m, 9H), 8.05 (s, 1H)

Example 654-(3,4-dimethoxyphenyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

4-(3,4-Dimethoxyphenyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.36 g) was suspended in isopropyl alcohol (15 mL), 2N potassiumhydroxide solution (0.32 mL) was added, and the solvent was evaporatedunder reduced pressure. The residue was solidified with diisopropylether to give the title compound as a colorless solid (0.36 g, 94%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.99 (t, J=7.5 Hz, 3H), 1.57-1.73 (m, 2H),2.95-3.07 (m, 2H), 3.72 (s, 3H), 3.82 (s, 3H), 3.95 (s, 2H), 6.97-7.10(m, 2H), 7.13 (d, J=2.3 Hz, 1H), 7.21-7.50 (m, 8H), 8.04 (s, 1H)

Example 666-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl-4-(thiophen-3-yl)[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.2 g), sodium hydrogencarbonate (1.9 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-[(5-oxo-7-propyl-4-thiophen-3-yl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.52 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.22 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.19 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.2 g,33%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.96 (t, J=7.6 Hz, 3H), 1.52-1.70 (m, 2H),2.94-3.05 (m, 2H), 4.00 (s, 2H), 7.20-7.29 (m, 3H), 7.33-7.39 (m, 2H),7.47-7.58 (m, 2H), 7.63-7.72 (m, 3H), 7.79 (d, J=1.5 Hz, 1H), 8.11 (s,1H), 12.38 (br. s., 1H)

Example 674-(4-acetylphenyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

To a solution (10 mL) of4-[4-(1-hydroxyethyl)phenyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.05 g) in methanol was added sodium borohydride (0.039 g), and themixture was stirred at room temperature for 1 hr. After evaporation ofthe solvent under reduced pressure, the residue was extracted with waterand ethyl acetate. The obtained ethyl acetate layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.036 g, 72%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.97 (t, J=7.2 Hz, 3H), 1.51-1.69 (m, 2H),2.65 (s, 3H), 2.92-3.07 (m, 2H), 4.02 (s, 2H), 7.24 (d, J=8.0 Hz, 2H),7.38 (d, J=8.0 Hz, 2H), 7.47-7.61 (m, 2H), 7.61-7.73 (m, 4H), 8.03-8.17(m, 3H), 12.38 (br. s., 1H)

Example 682-methyl-4-(1-methylpropyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.85 g), sodium hydrogencarbonate (1.4 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[2-methyl-4-(1-methylpropyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.36 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.16 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.13 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.064g, 16%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.75 (t, J=7.3 Hz, 3H), 0.91 (t, J=7.5 Hz,3H), 1.45-1.60 (m, 5H), 1.78-1.93 (m, 1H), 2.07-2.25 (m, 1H), 2.35 (s,3H), 2.83-2.93 (m, 2H), 3.95 (s, 2H), 4.93-5.11 (m, 1H), 7.20-7.31 (m,4H), 7.48-7.58 (m, 2H), 7.61-7.74 (m, 2H), 12.37 (br. s., 1H)

Example 692-methyl-4-[(1-methylcyclopropyl)methyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.83 g), sodium hydrogencarbonate (1.3 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-({2-methyl-4-[(1-methylcyclopropyl)methyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.36 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.16 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.13 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.16 g,40%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.25-0.31 (m, 2H), 0.71-0.78 (m, 2H), 0.92(t, J=7.2 Hz, 3H), 0.99 (s, 3H), 1.49-1.60 (m, 2H), 2.34 (s, 3H),2.86-2.95 (m, 2H), 3.96 (s, 2H), 4.06 (s, 2H), 7.19-7.25 (m, 2H),7.26-7.34 (m, 2H), 7.47-7.59 (m, 2H), 7.61-7.72 (m, 2H), 12.37 (br. s.,1H)

Example 706-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl-4-(thiophen-3-yl)[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

6-{[2′-(5-Oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl-4-(thiophen-3-yl)[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.2 g) was suspended in isopropyl alcohol (10 mL), 2N potassiumhydroxide solution (0.19 mL) was added, and the solvent was evaporatedunder reduced pressure. The residue was solidified with diisopropylether to give the title compound as a colorless solid (0.18 g, 86%).

¹H NMR (300 MHz, DMSO-d₆) δ 1.00 (t, J=7.6 Hz, 3H), 1.56-1.75 (m, 2H),2.95-3.08 (m, 2H), 3.95 (s, 2H), 7.20-7.50 (m, 9H), 7.65 (dd, J=5.3, 3.2Hz, 1H), 7.81 (dd, J=3.2, 1.3 Hz, 1H), 8.09 (s, 1H)

Example 714-(3-hydroxy-2,2-dimethylpropyl)-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.92 g), sodium hydrogencarbonate (1.51 g) and dimethyl sulfoxide (10 mL) was stirred at 50° C.for 30 min,4′-{[4-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.5 g) was added, and the mixture was stirred at 90° C. for 20 hr.After allowing to cool to room temperature, ethyl acetate and water wereadded to the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with water and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography, and dissolved in tetrahydrofuran (15mL). N,N′-Carbonyldiimidazole (0.17 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 mL) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 1 N hydrochloric acid and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (15 mL). Tetrabutylammonium fluoride (1 Mtetrahydrofuran solution, 2.2 mL) was added, and the mixture was stirredat room temperature for 3 hr. The reaction mixture was extracted withethyl acetate and water, and the organic layer was washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The obtained residuewas purified by silica gel column chromatography to give the titlecompound as a colorless amorphous solid (0.26 g, 56%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84-0.96 (m, 9H), 1.48-1.64 (m, 2H), 2.34(s, 3H), 2.85-2.95 (m, 2H), 3.08-3.15 (m, 2H), 3.96 (s, 2H), 4.02 (s,2H), 4.86 (t, J=6.3 Hz, 1H), 7.19-7.24 (m, 2H), 7.26-7.32 (m, 2H), 7.53(dd, J=17.7, 7.0 Hz, 2H), 7.62-7.72 (m, 2H), 12.37 (br. s., 1H)

Example 722-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[(1-phenylcyclopropyl)methyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.88 g), sodium hydrogencarbonate (1.4 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-({2-methyl-5-oxo-4-[(1-phenylcyclopropyl)methyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.43 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.16 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.069g, 14%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.89-0.99 (m, 2H) 1.05 (t, J=7.3 Hz,3H) 1.67-1.83 (m, 2H) 2.51 (s, 3H) 3.10-3.19 (m, 2H) 3.99 (s, 2H) 4.54(s, 2H) 7.07-7.39 (m, 10H) 7.47-7.67 (m, 2H) 7.84-7.91 (m, 1H)

Example 734-(3-methoxy-2,2-dimethylpropyl)-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

To a solution (10 mL) of4′-{[4-(3-hydroxy-2,2-dimethylpropyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.24 g) in methylene chloride were added tetrafluoroboric acid (42%aqueous solution, 0.15 mL) and trimethylsilyldiazomethane (2M hexanesolution, 0.51 mL), and the mixture was stirred at room temperature for1 hr. The reaction mixture was diluted with ethyl acetate, washed withwater and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure. The residueobtained by silica gel column chromatography was dissolved in dimethylsulfoxide (5 mL), and the mixture was added to a mixture ofhydroxylammonium chloride (0.33 g), sodium hydrogen carbonate (0.53 g)and dimethyl sulfoxide (5 mL), which had been stirred in advance at 40°C. for 30 min. The reaction mixture was stirred at 90° C. for 16 hr, anddiluted with ethyl acetate, and the mixture was washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.061 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.052 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.082g, 30%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.86-0.95 (m, 9H), 1.46-1.61 (m, 2H), 2.34(s, 3H), 2.85-2.95 (m, 2H), 3.13 (s, 5H), 3.95 (s, 2H), 4.08 (s, 2H),7.18-7.24 (m, 2H), 7.26-7.32 (m, 2H), 7.46-7.57 (m, 2H), 7.61-7.73 (m,2H), 12.37 (br. s., 1H)

Example 744-(cyclohex-2-en-1-yl)-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.67 g), sodium hydrogencarbonate (1.1 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{4-(cyclohex-2-en-1-yl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.3 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.13 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.15 g,43%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H) 1.45-2.17 (m, 6H)2.31-2.45 (m, 5H) 2.82-2.94 (m, 2H) 3.93 (s, 2H) 5.49-5.64 (m, 2H)5.75-5.84 (m, 1H) 7.18-7.26 (m, 2H) 7.28-7.33 (m, 2H) 7.47-7.59 (m, 2H)7.61-7.72 (m, 2H) 12.38 (br. s., 1H)

Example 754-(2-methoxy-3,3-dimethylbutyl)-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.47 g), sodium hydrogencarbonate (0.76 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[4-(2-methoxy-3,3-dimethylbutyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.22 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.087 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.074 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.058g, 23%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.87-0.99 (m, 12H) 1.47-1.64 (m, 2H) 2.37(s, 3H) 2.88-2.99 (m, 2H) 3.00 (s, 3H) 3.42 (dd, J=9.5, 3.1 Hz, 1H)3.93-4.00 (m, 2H) 4.08 (dd, J=13.4, 2.8 Hz, 1H) 4.34 (dd, J=13.4, 9.6Hz, 1H) 7.18-7.24 (m, 2H) 7.26-7.32 (m, 2H) 7.46-7.60 (m, 2H) 7.61-7.75(m, 2H) 12.37 (br. s., 1H)

Example 764-(2-hydroxy-3,3-dimethylbutyl)-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.6 g), sodium hydrogencarbonate (2.5 g) and dimethyl sulfoxide (10 mL) was stirred at 50° C.for 30 min,4′-{[4-(2-{[tert-butyl(dimethyl)silyl]oxy}-3,3-dimethylbutyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.9 g) was added, and the mixture was stirred at 90° C. for 20 hr.After allowing to cool to room temperature, ethyl acetate and water wereadded to the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with water and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography, and dissolved in tetrahydrofuran (15mL). N,N′-Carbonyldiimidazole (0.29 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 mL) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 1 N hydrochloric acid and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (15 mL). Tetrabutylammonium fluoride (1 Mtetrahydrofuran solution, 7.5 mL) was added and the mixture was stirredat 70° C. for 5 hr. The reaction mixture was extracted with ethylacetate and water, and the organic layer was washed with water and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography to give the title compoundas a colorless amorphous solid (0.59 g, 72%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.88-0.97 (m, 12H), 1.48-1.63 (m, 2H), 2.35(s, 3H), 2.81-2.96 (m, 2H), 3.66-3.76 (m, 1H), 3.95 (s, 2H), 3.97-4.06(m, 1H), 4.26 (dd, J=12.9, 10.3 Hz, 1H), 4.70 (d, J=5.5 Hz, 1H),7.18-7.25 (m, 2H), 7.26-7.33 (m, 2H), 7.44-7.59 (m, 2H), 7.61-7.73 (m,2H), 12.39 (br. s., 1H)

Example 774-(3,3-dimethyl-2-oxobutyl)-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4-(2-hydroxy-3,3-dimethylbutyl)-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.52 g), Dess-Martin reagent (0.81 g) and acetonitrile (15 mL) wasstirred at room temperature for 3 hr. Saturated aqueous sodium hydrogencarbonate and sodium thiosulfate-pentahydrate were added to the reactionmixture, and the mixture was stirred at room temperature for 2 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless amorphous solid (0.43 g, 85%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H), 1.22 (s, 9H),1.48-1.64 (m, 2H), 2.32 (s, 3H), 2.94 (dd, J=9.0, 6.6 Hz, 2H), 3.95 (s,2H), 5.16 (s, 2H), 7.25 (q, J=8.4 Hz, 4H), 7.47-7.58 (m, 2H), 7.63-7.72(m, 2H), 12.37 (s, 1H)

Example 784-cyclohexyl-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

To a solution (10 mL) of4′-{4-(cyclohex-2-en-1-yl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-ylmethyl}biphenyl-2-carbonitrile(0.59 g) in ethyl acetate was added 10% palladium-carbon (containingwater by 50%, 0.1 g), and the mixture was stirred under a hydrogenatmosphere for 4 hr. The reaction mixture was diluted with ethylacetate, the insoluble material was filtered off through celite, and thesolvent was evaporated under reduced pressure. The residue was added toa mixture of hydroxylammonium chloride (1.1 g), sodium hydrogencarbonate (1.8 g) and dimethyl sulfoxide (5 mL), which had been stirredat 40° C. for 30 min in advance, and the mixture was stirred at 90° C.for 18 hr. After allowing to cool to room temperature, ethyl acetate andwater were added to the reaction mixture, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated brine,and dried over anhydrous magnesium sulfate, and the solvent wasevaporated. The residue was dissolved in tetrahydrofuran (15 mL).N,N′-Carbonyldiimidazole (0.21 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.18 mL) were added, and the mixturewas stirred at room temperature for 3 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 1 N hydrochloric acid and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless amorphous solid (0.35 g, 62%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H), 1.10-1.44 (m, 3H),1.46-1.58 (m, 2H), 1.58-1.71 (m, 3H), 1.75-1.89 (m, 2H), 2.35 (s, 3H),2.41-2.56 (m, 2H), 2.83-2.94 (m, 2H), 3.93 (s, 2H), 4.77-4.93 (m, 1H),7.17-7.24 (m, 2H), 7.25-7.32 (m, 2H), 7.46-7.60 (m, 2H), 7.61-7.74 (m,2H), 12.37 (s, 1H)

Example 794-[(2Z)-2-(methoxyimino)-3,3-dimethylbutyl]-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4-(3,3-dimethyl-2-oxobutyl)-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.3 g), (aminooxy)methane hydrochloride (0.93 g) and pyridine (10 mL)was stirred at 110° C. for 16 hr. Ethyl acetate and water were added tothe reaction mixture, and the mixture was adjusted to pH 4 with 1 Nhydrochloric acid. The ethyl acetate layer was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography to give the title compound as colorlesscrystals (0.16 g, 49%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.87 (t, J=7.3 Hz, 3H), 1.17 (s, 9H),1.44-1.61 (m, 2H), 2.34 (s, 3H), 2.85-2.98 (m, 2H), 3.36 (s, 3H), 3.94(s, 2H), 4.91 (s, 2H), 7.16-7.31 (m, 4H), 7.45-7.59 (m, 2H), 7.61-7.73(m, 2H), 12.37 (s, 1H)

Example 802-methyl-4-[(3-methyloxetan-3-yl)methyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.67 g), sodium hydrogencarbonate (1.1 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-({2-methyl-4-[(3-methyloxetan-3-yl)methyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.3 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.12 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.079g, 23%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H), 1.25 (s, 3 H),1.45-1.63 (m, 2H), 2.34 (s, 3H), 2.87-2.95 (m, 2H), 3.96 (s, 2H), 4.14(d, J=6.0 Hz, 2H), 4.28 (s, 2H), 4.66 (d, J=6.0 Hz, 2H), 7.18-7.24 (m,2H), 7.26-7.32 (m, 2H), 7.46-7.59 (m, 2H), 7.62-7.72 (m, 2H), 12.37 (s,1H)

Example 812-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl-4-(tetrahydro-2H-pyran-4-yl)[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.83 g), sodium hydrogencarbonate (1.3 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[2-methyl-5-oxo-7-propyl-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.37 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.16 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.13 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.23 g,55%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H), 1.46-1.63 (m, 4H),2.37 (s, 3H), 2.66-2.93 (m, 4H), 3.43 (t, J=11.3 Hz, 2H), 3.90-4.02 (m,4H), 5.05-5.20 (m, 1H), 7.19-7.24 (m, 2H), 7.27-7.33 (m, 2H), 7.45-7.59(m, 2H), 7.61-7.74 (m, 2H), 12.37 (s, 1H)

Example 824-(2-methoxy-1-methylethyl)-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.4 g), sodium hydrogencarbonate (2.3 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[4-(2-methoxy-1-methylethyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.63 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.27 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.39 g,55%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H), 1.45 (d, J=7.0 Hz,3H), 1.47-1.60 (m, 2H), 2.35 (s, 3H), 2.82-2.96 (m, 2H), 3.18 (s, 3H),3.57 (dd, J=10.0, 5.5 Hz, 1H), 3.94 (s, 2H), 4.16 (t, J=9.7 Hz, 1H),5.29 (br. s., 1H), 7.19-7.31 (m, 4H), 7.44-7.58 (m, 2H), 7.60-7.74 (m,2H), 12.37 (s, 1H)

Example 834-cyclobutyl-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.4 g), sodium hydrogencarbonate (2.2 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-[(4-cyclobutyl-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.58 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.26 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.22 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.38 g,57%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H), 1.46-1.61 (m, 2H),1.68-1.97 (m, 2H), 2.08-2.25 (m, 2H), 2.38 (s, 3H), 2.81-2.94 (m, 2H),3.03-3.19 (m, 2H), 3.92 (s, 2H), 5.32-5.51 (m, 1H), 7.18-7.25 (m, 2H),7.24-7.34 (m, 2H), 7.44-7.59 (m, 2H), 7.60-7.74 (m, 2H), 12.37 (br. s.,1H)

Example 844-(2-hydroxypropyl)-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.6 g), sodium hydrogencarbonate (2.5 g) and dimethyl sulfoxide (10 mL) was stirred at 50° C.for 30 min,4′-{[4-(2-{[tert-butyl(dimethyl)silyl]oxy}-3,3-dimethylbutyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.9 g) was added, and the mixture was stirred at 90° C. for 20 hr.After allowing to cool to room temperature, ethyl acetate and water wereadded to the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with water and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography, and dissolved in tetrahydrofuran (15mL). N,N′-Carbonyldiimidazole (0.29 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 mL) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 1 N hydrochloric acid and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (15 mL). Tetrabutylammonium fluoride (1 Mtetrahydrofuran solution, 7.5 mL) was added and the mixture was stirredat 70° C. for 5 hr. The reaction mixture was extracted with ethylacetate and water, and the organic layer was washed with water and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography to give the title compoundas a colorless amorphous solid (0.59 g, 72%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.5 Hz, 3H), 1.09 (d, J=5.8 Hz,3H), 1.47-1.62 (m, 2H), 2.34 (s, 3H), 2.84-2.93 (m, 2H), 3.86-3.97 (m,3H), 4.09-4.20 (m, 2H), 4.83 (d, J=4.7 Hz, 1H), 7.17-7.24 (m, 2H),7.26-7.33 (m, 2H), 7.47-7.59 (m, 2H), 7.62-7.72 (m, 2H), 12.38 (s, 1H)

Example 852-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-(2-oxopropyl)-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4-(2-hydroxypropyl)-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.42 g), Dess-Martin reagent (0.71 g) and acetonitrile (10 mL) wasstirred at room temperature for 3 hr. Saturated aqueous sodium hydrogencarbonate and sodium thiosulfate-pentahydrate were added to the reactionmixture, and the mixture was stirred at room temperature for 2 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas colorless crystals (0.26 g, 62%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H), 1.45-1.63 (m, 2H),2.27 (s, 3H), 2.32 (s, 3H), 2.88-3.00 (m, 2H), 3.95 (s, 2H), 5.02 (s,2H), 7.19-7.32 (m, 4H), 7.46-7.59 (m, 2H), 7.61-7.74 (m, 2H), 12.38 (br.s., 1H)

Example 864-(2-cyclohexyl-2-hydroxyethyl)-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.3 g), sodium hydrogencarbonate (2.1 g) and dimethyl sulfoxide (10 mL) was stirred at 50° C.for 30 min,4′-{[4-(2-{[tert-butyl(dimethyl)silyl]oxy}-2-cyclohexylethyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.76 g) was added, and the mixture was stirred at 90° C. for 20 hr.After allowing to cool to room temperature, ethyl acetate and water wereadded to the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with water and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography, and dissolved in tetrahydrofuran (15mL). N,N′-Carbonyldiimidazole (0.24 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 mL) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 1 N hydrochloric acid and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). Tetrabutylammonium fluoride (1 Mtetrahydrofuran solution, 3.1 mL) was added and the mixture was stirredat 70° C. for 5 hr. The reaction mixture was extracted with ethylacetate and water, and the organic layer was washed with water and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography to give the title compoundas a colorless amorphous solid (0.6 g, 86%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H), 1.03-1.90 (m, 13H),2.34 (s, 3H), 2.83-2.95 (m, 2H), 3.74-3.86 (m, 1H), 3.91-4.07 (m, 3H),4.15-4.25 (m, 1H), 4.66 (d, J=5.5 Hz, 1H), 7.18-7.25 (m, 2H), 7.27-7.33(m, 2H), 7.46-7.59 (m, 2H), 7.62-7.72 (m, 2H), 12.38 (br. s., 1H)

Example 874-(2-cyclohexyl-2-oxoethyl)-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4-(2-cyclohexyl-2-hydroxyethyl)-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.6 g), Dess-Martin reagent (0.89 g) and acetonitrile (10 mL) wasstirred at room temperature for 3 hr. Saturated aqueous sodium hydrogencarbonate and sodium thiosulfate-pentahydrate were added to the reactionmixture, and the mixture was stirred at room temperature for 2 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas colorless crystals (0.52 g, 87%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H), 1.09-1.40 (m, 5H),1.47-1.66 (m, 3H), 1.68-1.78 (m, 2H), 1.84-1.98 (m, 2H), 2.32 (s, 3H),2.58-2.73 (m, 1H), 2.87-2.98 (m, 2H), 3.94 (s, 2H), 5.06 (s, 2H),7.17-7.31 (m, 4H), 7.45-7.58 (m, 2H), 7.60-7.72 (m, 2H), 12.37 (br. s.,1H)

Example 884-[(2E)-2-(ethoxyimino)-3,3-dimethylbutyl]-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4-(3,3-dimethyl-2-oxobutyl)-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.3 g), (aminooxy)ethane hydrochloride (1.1 g) and pyridine (10 mL) wasstirred at 110° C. for 16 hr. Ethyl acetate and water were added to thereaction mixture, and the mixture was adjusted to pH 4 with 1 Nhydrochloric acid. The ethyl acetate layer was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.16 g, 49%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.56 (t, J=7.1 Hz, 3H) 0.90 (t, J=7.3 Hz,3H) 1.19 (s, 9H) 1.43-1.57 (m, 2H) 2.34 (s, 3H) 2.82-2.95 (m, 2H) 3.60(q, J=7.0 Hz, 2H) 3.94 (s, 2H) 4.89 (s, 2H) 7.18-7.30 (m, 4H) 7.46-7.59(m, 2H) 7.60-7.73 (m, 2H) 12.37 (s, 1H)

Example 894-[(2Z)-2-cyclohexyl-2-(methoxyimino)ethyl]-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4-(2-cyclohexyl-2-oxoethyl)-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.25 g), (aminooxy)methane hydrochloride (0.74 g) and pyridine (10 mL)was stirred at 110° C. for 16 hr. Ethyl acetate and water were added tothe reaction mixture, and the mixture was adjusted to pH 4 with 1 Nhydrochloric acid. The ethyl acetate layer was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.067 g, 26%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.85-1.27 (m, 8H), 1.47-1.67 (m, 7H),1.72-1.85 (m, 1H), 2.35 (s, 3H), 2.86-3.01 (m, 2H), 3.74 (s, 3H), 3.97(s, 2H), 4.93 (s, 2H), 7.15-7.29 (m, 4H), 7.43-7.59 (m, 2H), 7.62-7.72(m, 2H), 12.38 (s, 1H)

Example 904-[(2E)-2-cyclohexyl-2-(methoxyimino)ethyl]-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4-(2-cyclohexyl-2-oxoethyl)-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.25 g), (aminooxy)methane hydrochloride (0.74 g) and pyridine (10 mL)was stirred at 110° C. for 16 hr. Ethyl acetate and water were added tothe reaction mixture, and the mixture was adjusted to pH 4 with 1 Nhydrochloric acid. The ethyl acetate layer was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography to give the title compound as colorlesscrystals (0.066 g, 26%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.88 (t, J=7.3 Hz, 3H), 1.17-1.59 (m, 7H),1.61-1.81 (m, 5H), 2.34 (s, 3H), 2.86-3.02 (m, 3H), 3.51 (s, 3H), 3.96(s, 2H), 4.84 (s, 2H), 7.17-7.29 (m, 4H), 7.44-7.59 (m, 2H), 7.60-7.73(m, 2H), 12.37 (s, 1H)

Example 914-[(2Z)-2-(methoxyimino)propyl]-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-(2-oxopropyl)-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.2 g), (aminooxy)methane hydrochloride (0.67 g) and pyridine (10 mL)was stirred at 110° C. for 16 hr. Ethyl acetate and water were added tothe reaction mixture, and the mixture was adjusted to pH 4 with 1 Nhydrochloric acid. The ethyl acetate layer was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography to give the title compound as colorlesscrystals (0.016 g, 8%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H), 1.48-1.64 (m, 5H),2.36 (s, 3H), 2.87-2.98 (m, 2H), 3.80 (s, 3H), 3.97 (s, 2H), 4.90 (s,2H), 7.17-7.25 (m, 2H), 7.26-7.33 (m, 2H), 7.47-7.58 (m, 2H), 7.62-7.71(m, 2H), 12.38 (br. s., 1H)

Example 924-[(2E)-2-(ethoxyimino)-3,3-dimethylbutyl]-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4-(3,3-dimethyl-2-oxobutyl)-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.3 g), (aminooxy)ethane hydrochloride (1.1 g) and pyridine (10 mL) wasstirred at 110° C. for 16 hr. Ethyl acetate and water were added to thereaction mixture, and the mixture was adjusted to pH 4 with 1 Nhydrochloric acid. The ethyl acetate layer was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography to give the title compound as colorlesscrystals (0.024 g, 7%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83-0.93 (m, 6H), 1.27 (s, 9H), 1.44-1.61(m, 2H), 2.33 (s, 3H), 2.87-2.96 (m, 2H), 3.66 (q, J=7.0 Hz, 2H), 3.96(s, 2H), 4.88 (s, 2H), 7.16-7.29 (m, 4H), 7.45-7.58 (m, 2H), 7.62-7.73(m, 2H)

Example 934-[(2E)-2-(methoxyimino)propyl]-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-(2-oxopropyl)-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.2 g), (aminooxy)methane hydrochloride (0.67 g) and pyridine (10 mL)was stirred at 110° C. for 16 hr. Ethyl acetate and water were added tothe reaction mixture, and the mixture was adjusted to pH 4 with 1 Nhydrochloric acid. The ethyl acetate layer was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.071 g, 34%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.2 Hz, 3H), 1.46-1.65 (m, 2H),1.80 (s, 3H), 2.35 (s, 3H), 2.83-2.97 (m, 2H), 3.62 (s, 3H), 3.96 (s,2H), 4.80 (s, 2H), 7.17-7.32 (m, 4H), 7.52 (dd, J=16.8, 7.4 Hz, 2H),7.60-7.74 (m, 2H), 12.37 (br. s., 1H)

Example 944-[(2Z)-2-(methoxyimino)-3,3-dimethylbutyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4-(3,3-dimethyl-2-oxobutyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.1 g), (aminooxy)methane hydrochloride (0.32 g) and pyridine (5 mL)was stirred at 110° C. for 16 hr. Ethyl acetate and water were added tothe reaction mixture, and the mixture was adjusted to pH 4 with 1 Nhydrochloric acid. The ethyl acetate layer was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography to give the title compound as colorlesscrystals (0.022 g, 21%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.88 (t, J=7.4 Hz, 3H), 1.15 (s, 9H),1.45-1.61 (m, 2H), 2.90-3.05 (m, 2H), 3.35 (s, 3H), 3.97 (s, 2H), 4.96(s, 2H), 7.19-7.32 (m, 4H), 7.52 (dd, J=17.6, 7.8 Hz, 2H), 7.59-7.73 (m,2H), 8.18 (s, 1H), 12.37 (br. s., 1H)

Example 952-methyl-4-(1-methylpropyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-(trifluoromethyl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate(1.84 g) and 5-methyl-N-(1-methylpropyl)-4H-1,2,4-triazol-3-amine (0.4g) was stirred under microwave irradiation at 250° C. for 15 min. Theresidue obtained by silica gel column chromatography was dissolved indimethyl sulfoxide (5 mL), and the mixture was added to a mixture ofhydroxylammonium chloride (0.8 g), sodium hydrogen carbonate (1.3 g) anddimethyl sulfoxide (10 mL), which had been stirred in advance at 40° C.for 30 min. The reaction mixture was stirred at 90° C. for 16 hr,diluted with ethyl acetate, washed with water and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography, and dissolved in tetrahydrofuran (10mL). N,N′-Carbonyldiimidazole (0.15 g) and then with1,8-diazabicyclo[5.4.0]undec-7-ene (0.13 mL) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.26 g,32%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.76 (t, J=7.4 Hz, 3H), 0.88 (t, J=7.4 Hz,3H), 1.45-1.66 (m, 5H), 1.77-1.91 (m, 1H), 2.08-2.26 (m, 1H), 2.38 (s,3H), 2.73-2.85 (m, 2H), 4.07 (s, 2H), 4.89-5.08 (m, 1H), 7.22 (d, J=8.0Hz, 1H), 7.41 (d, J=8.3 Hz, 1H), 7.53-7.77 (m, 5H), 12.47 (br. s., 1H)

Example 964-{(2Z)-3,3-dimethyl-2-[(1-methylethoxy)imino]butyl}-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-(2-oxopropyl)-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.3 g), 2-(aminooxy)propane hydrochloride (0.93 g) and pyridine (10 mL)was stirred at 110° C. for 16 hr. Ethyl acetate and water were added tothe reaction mixture, and the mixture was adjusted to pH 4 with 1 Nhydrochloric acid. The ethyl acetate layer was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography to give the title compound as colorlesscrystals (0.11 g, 33%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.62 (d, J=6.0 Hz, 6H), 0.92 (t, J=7.3 Hz,3H), 1.21 (s, 9H), 1.44-1.57 (m, 2H), 2.34 (s, 3H), 2.84-2.96 (m, 2H),3.26-3.36 (m, 1H), 3.93 (s, 2 H), 4.86 (s, 2H), 7.15-7.30 (m, 4H),7.44-7.58 (m, 2H), 7.60-7.72 (m, 2H), 12.38 (br. s., 1H)

Example 974-{(2E)-3,3-dimethyl-2-[(1-methylethoxy)imino]butyl}-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-(2-oxopropyl)-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.3 g), 2-(aminooxy)propane hydrochloride (0.93 g) and pyridine (10 mL)was stirred at 110° C. for 16 hr. Ethyl acetate and water were added tothe reaction mixture, and the mixture was adjusted to pH 4 with 1 Nhydrochloric acid. The ethyl acetate layer was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography to give the title compound as colorlesscrystals (0.017 g, 5%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83-0.92 (m, 9H), 1.27 (s, 9H), 1.44-1.58(m, 2H), 2.32 (s, 3H), 2.85-2.96 (m, 2H), 3.66-3.81 (m, 1H), 3.95 (s,2H), 4.88 (s, 2H), 7.17-7.28 (m, 4H), 7.45-7.58 (m, 2H), 7.61-7.74 (m,2H), 12.37 (br. s., 1H)

Example 984-[(2Z)-2-(tert-butoxyimino)-3,3-dimethylbutyl]-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-(2-oxopropyl)-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.3 g), 2-(aminooxy)-2-methylpropane hydrochloride (1.1 g) and pyridine(10 mL) was stirred at 110° C. for 16 hr. Ethyl acetate and water wereadded to the reaction mixture, and the mixture was adjusted to pH 4 with1 N hydrochloric acid. The ethyl acetate layer was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography to give the title compound as colorlessamorphous crystals (0.074 g, 22%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.76 (s, 9H), 0.91 (t, J=7.3 Hz, 3H), 1.22(s, 9H), 1.44-1.57 (m, 2H), 2.33 (s, 3H), 2.82-2.94 (m, 2H), 3.92 (s,2H), 4.84 (s, 2H), 7.16-7.30 (m, 4H), 7.44-7.58 (m, 2H), 7.60-7.71 (m,2H), 12.37 (br. s., 1H)

Example 994-[(2E)-2-(tert-butoxyimino)-3,3-dimethylbutyl]-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-(2-oxopropyl)-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.3 g), 2-(aminooxy)-2-methylpropane hydrochloride (1.1 g) and pyridine(10 mL) was stirred at 110° C. for 16 hr. Ethyl acetate and water wereadded to the reaction mixture, and the mixture was adjusted to pH 4 with1 N hydrochloric acid. The ethyl acetate layer was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography to give the title compound as colorlessamorphous crystals (0.069 g, 20%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (s, 9H), 0.89 (t, J=7.3 Hz, 3H), 1.26(s, 9H), 1.44-1.63 (m, 2H), 2.31 (s, 3H), 2.86-2.99 (m, 2H), 3.94 (s,2H), 4.88 (s, 2H), 7.14-7.32 (m, 4H), 7.44-7.59 (m, 2H), 7.61-7.73 (m,2H), 12.39 (br. s., 1H)

Example 1002-(methoxymethyl)-4-(1-methylpropyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.45 g), sodium hydrogencarbonate (0.73 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[2-(methoxymethyl)-4-(1-methylpropyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.2 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.072 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.084 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.11 g,49%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.76 (t, J=7.3 Hz, 3H) 1.46-1.61 (m, 5H)1.81-1.95 (m, 1H) 2.07-2.24 (m, 1H) 2.87-2.95 (m, 2H) 3.32 (s, 4H) 3.36(s, 3H) 3.96 (s, 2H) 4.47 (s, 2H) 4.95-5.11 (m, 1H) 7.19-7.24 (m, 2H)7.27-7.31 (m, 2H) 7.47-7.58 (m, 2H) 7.61-7.71 (m, 2H) 12.37 (s, 1H)

Example 1012-(hydroxymethyl)-4-(1-methylpropyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of2-(methoxymethyl)-4-(1-methylpropyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.07 g), boron tribromide (1.0 M dichloromethane solution, 0.4 mL) anddichloromethane (5 mL) was stirred at room temperature for 2 hr,saturated aqueous sodium hydrogen carbonate (10 mL) was added, and themixture was further stirred for 1 hr. The reaction mixture was adjustedto pH 5 with 1 N hydrochloric acid, and the mixture was extracted withethyl acetate. The ethyl acetate layer was washed with saturated brine,and dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography to give the title compound as colorless crystals(0.02 g, 29%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.76 (t, J=7.4 Hz, 3H) 0.92 (t, J=7.3 Hz,3H) 1.48-1.61 (m, 5H) 1.80-1.94 (m, 1H) 2.09-2.27 (m, 1H) 2.85-2.97 (m,2H) 3.96 (s, 2H) 4.50 (d, J=6.0 Hz, 2H) 4.95-5.09 (m, 1H) 5.45 (t, J=6.1Hz, 1H) 7.18-7.31 (m, 4H) 7.46-7.59 (m, 2H) 7.61-7.74 (m, 2H) 12.37 (s,1H)

Example 1022-(bromomethyl)-4-(1-methylpropyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of2-(methoxymethyl)-4-(1-methylpropyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.07 g), boron tribromide (1.0 M dichloromethane solution, 0.4 mL) anddichloromethane (5 mL) was stirred at room temperature for 2 hr,saturated aqueous sodium hydrogen carbonate (10 mL) was added, and themixture was further stirred for 1 hr. The reaction mixture was adjustedto pH 5 with 1 N hydrochloric acid, and the mixture was extracted withethyl acetate. The ethyl acetate layer was washed with saturated brine,and dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography to give the title compound as colorless crystals(0.013 g, 2%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.76 (t, J=7.3 Hz, 3H), 0.92 (t, J=7.3 Hz,3H), 1.47-1.61 (m, 5H), 1.79-1.93 (m, 1H), 2.05-2.24 (m, 1H), 2.81-2.96(m, 2H), 3.96 (s, 2H), 4.69 (s, 2H), 4.92-5.08 (m, 1H), 7.19-7.33 (m,4H), 7.47-7.59 (m, 2H), 7.61-7.74 (m, 2H), 12.37 (s, 1H)

Example 1032-methyl-4-{(2Z)-2-[(1-methylethoxy)imino]propyl}-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-(2-oxopropyl)-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.4 g), 2-(aminooxy)propane hydrochloride (1.8 g) and pyridine (10 mL)was stirred at 110° C. for 16 hr. Ethyl acetate and water were added tothe reaction mixture, and the mixture was adjusted to pH 4 with 1 Nhydrochloric acid. The ethyl acetate layer was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography to give the title compound as colorlesscrystals (0.059 g, 11%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H), 1.10 (d, J=6.2 Hz,6H), 1.47-1.60 (m, 2H), 1.63 (s, 3H), 2.35 (s, 3H), 2.89-3.00 (m, 2H),3.96 (s, 2H), 4.10-4.25 (m, 1H), 4.86 (s, 2H), 7.18-7.33 (m, 4H),7.44-7.60 (m, 2H), 7.58-7.74 (m, 2H), 12.38 (br. s., 1H)

Example 1042-methyl-4-{(2E)-2-[(1-methylethoxy)imino]propyl}-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-(2-oxopropyl)-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.4 g), 2-(aminooxy)propane hydrochloride (1.8 g) and pyridine (10 mL)was stirred at 110° C. for 16 hr. Ethyl acetate and water were added tothe reaction mixture, and the mixture was adjusted to pH 4 with 1 Nhydrochloric acid. The ethyl acetate layer was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography to give the title compound as colorlesscrystals (0.2 g, 36%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.88 (t, J=7.3 Hz, 3H), 1.00 (d, J=6.2 Hz,6H), 1.46-1.59 (m, 2H), 1.80 (s, 3H), 2.33 (s, 3H), 2.86-2.97 (m, 2H),3.90-4.05 (m, 3H), 4.81 (s, 2 H), 7.15-7.33 (m, 4H), 7.46-7.59 (m, 2H),7.61-7.72 (m, 2H), 12.37 (s, 1H)

Example 1052-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl-4-(3,3,3-trifluoro-2-hydroxypropyl)[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.6 g), sodium hydrogencarbonate (2.6 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[2-methyl-5-oxo-7-propyl-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.76 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.025 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.21 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.41 g, 49%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91 (t, J=7.3 Hz, 3H), 1.44-1.62 (m, 2H),2.37 (s, 3H), 2.83-3.02 (m, 2H), 3.96 (s, 2H), 4.20 (dd, J=13.4, 4.0 Hz,1H), 4.38-4.49 (m, 1H), 4.61 (br. s., 1H), 6.59 (d, J=6.2 Hz, 1H),7.15-7.32 (m, 4H), 7.52 (dd, J=17.0, 7.5 Hz, 2H), 7.60-7.72 (m, 2H),12.39 (br. s., 1H)

Example 1062-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl-4-(3,3,3-trifluoro-2-oxopropyl)[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl-4-(3,3,3-trifluoro-2-hydroxypropyl)[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.41 g), Dess-Martin reagent(0.47 g) and acetonitrile (10 mL) was stirred at room temperature for 3hr. Saturated aqueous sodium hydrogen carbonate and sodiumthiosulfate-pentahydrate were added to the reaction mixture, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.18 g, 43%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H), 1.46-1.61 (m, 2H),2.37 (s, 3H), 2.85-2.97 (m, 2H), 3.98 (s, 2H), 4.50 (s, 2H), 7.19-7.25(m, 2H), 7.27-7.34 (m, 2H), 7.46-7.58 (m, 2H), 7.62-7.72 (m, 2H), 12.39(br. s., 1H)

Example 1074-[(2E)-2-(ethoxyimino)-3,3,3-trifluoropropyl]-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl-4-(3,3,3-trifluoro-2-oxopropyl)[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.14 g), 2-(aminooxy)ethanehydrochloride (0.37 g) and pyridine (5 mL) was stirred at 110° C. for 16hr. Ethyl acetate and water were added to the reaction mixture, and themixture was adjusted to pH 4 with 1 N hydrochloric acid. The ethylacetate layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The obtained residue was purified by silica gel column chromatography togive the title compound as a colorless amorphous solid (0.041 g, 28%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.2 Hz, 3H), 0.98 (t, J=7.0 Hz,3H), 1.44-1.59 (m, 2H), 2.36 (s, 3H), 2.85-3.00 (m, 2H), 3.95 (s, 2H),4.12 (q, J=7.2 Hz, 2H), 5.12 (s, 2H), 7.17-7.28 (m, 4H), 7.46-7.58 (m,2H), 7.59-7.73 (m, 2H), 12.36 (br. s., 1H)

Example 1086-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-7-propyl-4-(tetrahydro-2H-pyran-4-yl)[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.92 g), sodium hydrogencarbonate (1.5 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,3′-fluoro-4′-{[2-methyl-5-oxo-7-propyl-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.43 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.17 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.23 g, 49%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.4 Hz, 3H), 1.51-1.63 (m, 4H),2.37 (s, 3H), 2.64-2.83 (m, 2H), 2.88 (dd, J=9.1, 6.4 Hz, 2H), 3.42 (t,J=11.4 Hz, 2H), 3.87-4.01 (m, 4H), 4.99-5.20 (m, 1H), 6.98 (dd, J=8.0,1.5 Hz, 1H), 7.10-7.29 (m, 2H), 7.56 (dd, J=16.7, 7.2 Hz, 2H), 7.63-7.77(m, 2H), 12.44 (s, 1H)

Example 1096-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl-4-(tetrahydro-2H-pyran-4-yl)[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.69 g), sodium hydrogencarbonate (1.1 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[5-oxo-7-propyl-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.3 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.13 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.19 g,56%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.4 Hz, 3H), 1.47-1.67 (m, 4H),2.68-2.86 (m, 2H), 2.88-2.99 (m, 2H), 3.43 (t, J=11.4 Hz, 2H), 3.92-4.02(m, 4H), 5.10-5.26 (m, 1H), 7.17-7.24 (m, 2H), 7.27-7.38 (m, 2H), 7.53(dd, J=17.4, 6.8 Hz, 2H), 7.63-7.73 (m, 2H), 8.20 (s, 1H), 12.37 (s, 1H)

Example 1104-(2-methoxycyclohexyl)-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.59 g), sodium hydrogencarbonate (0.92 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[4-(2-methoxycyclohexyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.27 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.11 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.09 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.16 g,53%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.4 Hz, 3H), 1.21-1.62 (m, 6H),1.78 (dd, J=32.0, 10.4 Hz, 2H), 2.03 (d, J=11.4 Hz, 1H), 2.33 (s, 3H),2.91 (t, J=7.8 Hz, 2H), 3.03 (s, 3H), 3.22-3.40 (m, 1H), 3.61 (br. s.,1H), 3.83-4.04 (m, 2H), 4.76 (d, J=12.9 Hz, 1H), 7.17-7.33 (m, 4H), 7.52(dd, J=17.2, 7.4 Hz, 2H), 7.61-7.73 (m, 2H), 12.37 (br. s., 1H)

Example 1112-methyl-4-(1-methyl-2-oxopropyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (2.7 g), sodium hydrogencarbonate (4.4 g) and dimethyl sulfoxide (25 mL) was stirred at 50° C.for 30 min,4′-{[4-(2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylpropyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(1.5 g) was added, and the mixture was stirred at 90° C. for 20 hr.After allowing to cool to room temperature, the reaction mixture wasextracted with ethyl acetate and water, and the organic layer was washedwith water and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography, anddissolved in tetrahydrofuran (30 mL). N,N′-Carbonyldiimidazole (0.51 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.43 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 N hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was dissolved in tetrahydrofuran (30 mL). Tetrabutylammoniumfluoride (1 M tetrahydrofuran solution, 6.6 mL) was added, and themixture was stirred at room temperature for 3 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was extractedwith ethyl acetate. The organic layer was washed with water and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure. The residue obtained bysilica gel column chromatography was dissolved in acetonitrile (20 mL),Dess-Martin reagent (1.1 g) was added, and the mixture was stirred atroom temperature for 2 hr. Saturated aqueous sodium hydrogen carbonatesolution and sodium thiosulfate were added to the reaction mixture, andthe mixture was stirred at room temperature for 2 hr, and extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was recrystallized from acetone andhexane to give the title compound as colorless crystals (0.5 g, 37%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.4 Hz, 3H), 1.48-1.63 (m, 5H),2.08 (s, 3H), 2.35 (s, 3H), 2.86-2.99 (m, 2H), 5.36 (q, J=7.2 Hz, 1H),7.19-7.26 (m, 2H), 7.26-7.34 (m, 2H), 7.46-7.59 (m, 2H), 7.61-7.72 (m,2H), 12.37 (br. s., 1H)

Example 1126-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-(2-methoxy-1-methylethyl)-2-methyl-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.62 g), sodium hydrogencarbonate (0.99 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,3′-fluoro-4′-{[4-(2-methoxy-1-methylethyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.28 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.12 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.097 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.15 g,49%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.4 Hz, 3H) 1.44 (d, J=7.2 Hz,3H) 1.49-1.63 (m, 2H) 2.36 (s, 3H) 2.83-2.95 (m, 2H) 3.17 (s, 3H)3.51-3.60 (m, 1H) 3.93 (s, 2H) 5.16-5.40 (m, 1H) 7.00 (dd, J=8.0, 1.9Hz, 1H) 7.11-7.24 (m, 2H) 7.51-7.64 (m, 2H) 7.62-7.77 (m, 2H) 12.45 (br.s., 1H)

Example 1136-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-7-propyl-4-(tetrahydro-2H-thiopyran-4-yl)[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.1 g), sodium hydrogencarbonate (1.8 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,3′-fluoro-4′-{[2-methyl-5-oxo-7-propyl-4-(tetrahydro-2H-thiopyran-4-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.54 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.21 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.18 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.41 g,68%).

¹H NMR (300 MHz, DMSO-d₆) d ppm 0.92 (t, J=7.3 Hz, 3H), 1.46-1.64 (m,2H), 1.87-1.99 (m, 2H), 2.37 (s, 3H), 2.63-2.96 (m, 8H), 3.92 (s, 2H),4.85 (br. s., 1H), 6.98 (dd, J=8.0, 1.8 Hz, 1H), 7.16 (dd, J=11.1, 1.7Hz, 1H), 7.23 (t, J=8.0 Hz, 1H), 7.49-7.63 (m, 2H), 7.64-7.74 (m, 2H),12.45 (s, 1H)

Example 1144-[(2E)-2-(ethoxyimino)-1-methylpropyl]-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of2-methyl-4-(1-methyl-2-oxopropyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.2 g), (aminooxy)ethane hydrochloride (0.76 g) and pyridine (5 mL) wasstirred at 100° C. for 48 hr. Ethyl acetate and water were added to thereaction mixture, and the mixture was adjusted to pH 4 with 1 Nhydrochloric acid. The ethyl acetate layer was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.14 g, 66%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91 (t, J=7.3 Hz, 3H), 1.12 (t, J=7.1 Hz,3H), 1.47-1.58 (m, 2H), 1.61-1.69 (m, 6H), 2.34 (s, 3H), 2.85-2.95 (m,2H), 3.88-4.04 (m, 4H), 5.61 (q, J=7.0 Hz, 1H), 7.17-7.30 (m, 4H),7.46-7.58 (m, 2H), 7.61-7.72 (m, 2H), 12.38 (br. s., 1H)

Example 1156-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-4-(1-oxidetetrahydro-2H-thiopyran-4-yl)-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of6-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-7-propyl-4-(tetrahydro-2H-thiopyran-4-yl)[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.35 g), m-chloroperbenzoic acid (0.22 g), acetonitrile (15 mL) anddimethylformamide (5 mL) was stirred at room temperature for 3 hr. Thereaction mixture was diluted with chloroform, washed with saturatedaqueous sodium hydrogen carbonate and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.18 g,49%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.4 Hz, 3H), 1.48-1.62 (m, 2H),1.88-2.00 (m, 2H), 2.37 (s, 3H), 2.76-2.98 (m, 6H), 3.29-3.44 (m, 2H),3.91 (s, 2H), 4.98-5.19 (m, 1H), 6.94-7.03 (m, 1H), 7.12-7.28 (m, 2H),7.49-7.61 (m, 2H), 7.64-7.76 (m, 2H), 12.47 (br. s., 1H)

Example 1164-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-6-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of6-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-7-propyl-4-(tetrahydro-2H-thiopyran-4-yl)[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.35 g), m-chloroperbenzoic acid (0.22 g), acetonitrile (15 mL) anddimethylformamide (5 mL) was stirred at room temperature for 3 hr. Thereaction mixture was diluted with chloroform, washed with saturatedaqueous sodium hydrogen carbonate and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.14 g,35%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H) 1.47-1.63 (m, 2H)1.95-2.07 (m, 2H) 2.38 (s, 3H) 2.83-2.92 (m, 2H) 3.03-3.26 (m, 4H)3.40-3.54 (m, 2H) 3.92 (s, 2H) 5.17-5.31 (m, 1H) 6.98 (dd, J=7.9, 1.7Hz, 1H) 7.16 (dd, J=11.1, 1.7 Hz, 1H) 7.25 (t, J=8.1 Hz, 1H) 7.51-7.62(m, 2H) 7.63-7.74 (m, 2H) 12.47 (s, 1H)

Example 1176-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl-4-(tetrahydro-2H-pyran-4-yl)[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.3 g), sodium hydrogencarbonate (2 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for30 min,3′-fluoro-4′-{[5-oxo-7-propyl-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.57 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.24 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.46 g,72%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.3 Hz, 3H), 1.50-1.66 (m, 4H),2.66-2.85 (m, 2H), 2.94 (dd, J=9.8, 5.8 Hz, 2H), 3.42 (t, J=11.3 Hz,2H), 3.87-4.01 (m, 4H), 5.06-5.22 (m, 1H), 6.99 (dd, J=7.9, 1.7 Hz, 1H),7.17 (dd, J=11.1, 1.7 Hz, 1H), 7.26 (t, J=8.0 Hz, 1H), 7.50-7.63 (m,2H), 7.64-7.76 (m, 2H), 8.22 (s, 1H), 12.47 (br. s., 1H)

Example 1184-[(2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]-6-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.67 g), sodium hydrogencarbonate (1.1 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-({4-[(2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)-3′-fluorobiphenyl-2-carbonitrile(0.33 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.12 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.25 g,68%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.4 Hz, 3H), 1.14 (d, J=6.1 Hz,6H), 1.48-1.69 (m, 4H), 2.25-2.40 (m, 5H), 2.84-2.93 (m, 2H), 3.49-3.62(m, 2H), 3.92 (s, 2H), 5.03-5.21 (m, 1H), 6.99 (dd, J=8.0, 1.9 Hz, 1H),7.16 (dd, J=11.0, 1.9 Hz, 1H), 7.23 (t, J=8.1 Hz, 1H), 7.49-7.62 (m,2H), 7.64-7.75 (m, 2H), 12.45 (s, 1H)

Example 1194-[(2R,4s,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]-6-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.11 g), sodium hydrogencarbonate (0.17 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-({4-[(2R,4s,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)-3′-fluorobiphenyl-2-carbonitrile(0.052 g) was added, and the mixture was stirred at 90° C. for 16 hr.The reaction mixture was diluted with ethyl acetate, washed with waterand then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was dissolved in tetrahydrofuran (5 mL).N,N′-Carbonyldiimidazole (0.02 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.017 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.035g, 61%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.2 Hz, 3H), 1.09 (d, J=6.4 Hz,6H), 1.46-1.60 (m, 4H), 2.34-2.47 (m, 5H), 2.82-2.91 (m, 2H), 3.92 (s,2H), 4.06-4.19 (m, 2H), 5.17-5.29 (m, 1H), 6.98 (dd, J=7.8, 1.7 Hz, 1H),7.12-7.27 (m, 2H), 7.50-7.62 (m, 2H), 7.64-7.75 (m, 2H), 12.45 (s, 1H)

Example 1206-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-7-propyl-4-(tetrahydrofuran-3-yl)[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of tetrahydrofuran-3-ol (2.5 g), pyridinium dichromate (16 g),molecular sieves 4A (16 g) and tetrahydrofuran (200 mL) was stirred atroom temperature for 3 hr. The reaction solution was diluted withdiethyl ether (200 mL), the insoluble material was filtered off throughsilica gel, and the filtrate was concentrated. The obtained residue wasdissolved in acetic acid (20 mL), 1H-1,2,4-triazol-3-amine (1.4 g) andsodium cyanoborohydride (4.5 g) were added, and the mixture was stirredat room temperature for 16 hr. Water was added to the reaction mixture,and the solvent was evaporated under reduced pressure. The obtainedresidue was poured into saturated aqueous sodium hydrogen carbonate, andthe mixture was extracted with a mixed solvent of ethyl acetate andisopropyl alcohol (3:1). The obtained extract was dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure. Amixture of the obtained residue and ethyl2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (0.79 g) wasstirred under microwave irradiation at 250° C. for 20 min. The reactionmixture was purified by silica gel column chromatography and theobtained residue was dissolved in dimethyl sulfoxide (5 mL), and themixture was added to a mixture of hydroxylammonium chloride (0.36 g),sodium hydrogen carbonate (0.58 g) and dimethyl sulfoxide (5 mL), whichhad been stirred in advance at 40° C. for 30 min. The reaction mixturewas stirred at 90° C. for 16 hr, diluted with ethyl acetate, washed withwater and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography, and dissolvedin tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.067 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.057 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.052 g, 0.3%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H), 1.48-1.66 (m, 2H),2.07-2.22 (m, 1H), 2.37 (s, 3H), 2.41-2.48 (m, 1H), 2.83-2.92 (m, 2H),3.81-3.96 (m, 5H), 4.09-4.20 (m, 1H), 5.51-5.66 (m, 1H), 6.99 (dd,J=8.0, 1.6 Hz, 1H), 7.12-7.28 (m, 2H), 7.51-7.62 (m, 2H), 7.64-7.73 (m,2H), 12.46 (br. s., 1H)

Example 1216-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl-4-(tetrahydro-2H-pyran-3-yl)[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.37 g), sodium hydrogencarbonate (0.6 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,3′-fluoro-4′-{[5-oxo-7-propyl-4-(tetrahydro-2H-pyran-3-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.17 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.07 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.059 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.11 g, 56%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H), 1.48-1.63 (m, 2H),1.65-1.89 (m, 3H), 2.64-2.82 (m, 1H), 2.87-3.00 (m, 2H), 3.25-3.42 (m,2H), 3.73-3.89 (m, 2H), 3.94 (s, 2H), 4.90-5.06 (m, 1H), 6.99 (dd,J=7.9, 1.9 Hz, 1H), 7.17 (dd, J=11.1, 1.7 Hz, 1H), 7.25 (t, J=8.0 Hz,1H), 7.49-7.62 (m, 2H), 7.64-7.74 (m, 2H), 8.20 (s, 1H), 12.46 (br. s.,1H)

Example 1224-(1,4-dioxaspiro[4.5]dec-8-yl)-6-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.62 g), sodium hydrogencarbonate (1 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for30 min,4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile(0.32 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.12 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.098 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.25 g, 75%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H), 1.50-1.82 (m, 8H),2.37 (s, 3H), 2.67-2.92 (m, 4H), 3.81-3.96 (m, 6H), 4.83-4.96 (m, 1H),6.99 (dd, J=8.0, 1.8 Hz, 1H), 7.12-7.27 (m, 2H), 7.50-7.63 (m, 2H),7.64-7.73 (m, 2H), 12.46 (br. s., 1H)

Example 1236-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-4-(4-oxocyclohexyl)-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4-(1,4-dioxaspiro[4.5]dec-8-yl)-6-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.25 g), 6N hydrochloric acid (2 mL) and tetrahydrofuran (10 mL) wasstirred at room temperature for 2 hr. The reaction mixture was pouredinto saturated aqueous sodium hydrogen carbonate, and the mixture wasadjusted to pH 4 with 1 N hydrochloric acid and extracted with ethylacetate. The obtained ethyl acetate layer was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was recrystallizedfrom ethyl acetate and hexane to give the title compound as colorlesscrystals (0.18 g, 74%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.4 Hz, 3H), 1.48-1.62 (m, 2H),1.93-2.04 (m, 2H), 2.24-2.39 (m, 5H), 2.56-2.72 (m, 2H), 2.76-2.95 (m,4H), 3.94 (s, 2H), 5.37-5.49 (m, 1H), 6.98 (dd, J=8.0, 1.9 Hz, 1H), 7.16(dd, J=11.2, 1.7 Hz, 1H), 7.25 (t, J=8.0 Hz, 1H), 7.50-7.62 (m, 2H),7.63-7.76 (m, 2H), 12.45 (s, 1H)

Example 1246-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl-4-(tetrahydro-2H-pyran-3-yl)[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.66 g), sodium hydrogencarbonate (1.1 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[5-oxo-7-propyl-4-(tetrahydro-2H-pyran-3-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.15 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.12 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.1 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.057 g, 18%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.2 Hz, 3H), 1.45-1.60 (m, 2H),1.63-1.96 (m, 3H), 2.64-2.84 (m, 1H), 2.87-2.97 (m, 2H), 3.32-3.41 (m,1H), 3.75-3.90 (m, 2H), 3.96 (s, 2H), 4.22 (t, J=10.6 Hz, 1H), 4.92-5.07(m, 1H), 7.18-7.25 (m, 2H), 7.28-7.36 (m, 2H), 7.53 (dd, J=16.1, 7.8 Hz,2H), 7.61-7.73 (m, 2H), 8.19 (s, 1H), 12.38 (s, 1H)

Example 1257-butyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-(tetrahydro-2H-pyran-4-yl)[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.2 g), sodium hydrogencarbonate (1.9 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,7-butyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-(tetrahydro-2H-pyran-4-yl)[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.52 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.22 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.18 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.29 g, 50%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (t, J=7.2 Hz, 3H), 1.29-1.41 (m, 2H),1.42-1.55 (m, 2H), 1.55-1.67 (m, 2H), 2.65-2.87 (m, 2H), 2.88-3.00 (m,2H), 3.43 (t, J=11.3 Hz, 2H), 3.93-4.04 (m, 4H), 5.09-5.25 (m, 1H),7.18-7.25 (m, 2H), 7.28-7.34 (m, 2H), 7.46-7.59 (m, 2H), 7.59-7.73 (m,2H), 8.20 (s, 1H), 12.39 (s, 1H)

Example 1264-[(2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.2 g), sodium hydrogencarbonate (1.9 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-({4-[(2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.54 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.22 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.18 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.41 g,69%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H), 1.14 (d, J=6.0 Hz,6H), 1.48-1.60 (m, 2H), 1.60-1.73 (m, 2H), 2.36 (q, J=12.0 Hz, 2H),2.89-2.98 (m, 2H), 3.51-3.63 (m, 2H), 3.96 (s, 2H), 5.12-5.29 (m, 1H),7.18-7.25 (m, 2H), 7.27-7.36 (m, 2H), 7.46-7.59 (m, 2H), 7.61-7.75 (m,2H), 8.19 (s, 1H), 12.38 (s, 1H)

Example 1274-[(2R,4s,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.21 g), sodium hydrogencarbonate (0.34 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-({4-[(2R,4s,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.098 g) was added, and the mixture was stirred at 90° C. for 16 hr.The reaction mixture was diluted with ethyl acetate, washed with waterand then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was dissolved in tetrahydrofuran (5 mL).N,N′-Carbonyldiimidazole (0.039 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.033 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.058g, 53%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H), 1.10 (d, J=6.2 Hz,6H), 1.48-1.69 (m, 4H), 2.37-2.48 (m, 2H), 2.86-2.98 (m, 2H), 3.98 (s,2H), 4.09-4.20 (m, 2H), 5.29 (t, J=7.1 Hz, 1H), 7.19-7.26 (m, 2H),7.28-7.35 (m, 2H), 7.47-7.58 (m, 2H), 7.61-7.71 (m, 2H), 8.17-8.21 (m,1H), 12.38 (s, 1H)

Example 1286-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-(4-hydroxycyclohexyl)-2-methyl-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

To a solution (5 mL) of6-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-4-(4-oxocyclohexyl)-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.1 g) in methanol was added sodium borohydride (0.014 g), and themixture was stirred at room temperature for 1 hr. After evaporation ofthe solvent under reduced pressure, the residue was extracted with waterand ethyl acetate. The obtained ethyl acetate layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.046 g, 46%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H) 1.20-1.42 (m, 4H)1.44-1.66 (m, 4H) 1.71-1.82, 1.88-1.97 (m, combined 2H) 2.36 (s, 3H)2.83-2.92 (m, 2H) 3.40-3.54, 3.82-3.88 (m, combined 1H) 3.91 (s, 2H)4.33-4.66 (m, 1H) 4.72-4.87 (m, 1H) 6.98 (dd, J=7.9, 1.7 Hz, 1H)7.10-7.27 (m, 2H) 7.49-7.63 (m, 2H) 7.64-7.75 (m, 2H) 12.45 (s, 1H)

Example 1296-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl-4-(tetrahydrofuran-3-yl)[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.42 g), sodium hydrogencarbonate (0.67 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[5-oxo-7-propyl-4-(tetrahydrofuran-3-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.18 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.078 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.066 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.025 g, 13%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H), 1.47-1.64 (m, 2H),2.06-2.24 (m, 1H), 2.42-2.48 (m, 1H), 2.87-2.99 (m, 2H), 3.82-4.00 (m,5H), 4.17 (q, J=7.7 Hz, 1H), 5.57-5.72 (m, 1H), 7.20-7.25 (m, 2H),7.30-7.35 (m, 2 H), 7.48-7.58 (m, 2H), 7.62-7.73 (m, 2H), 8.20 (s, 1H),12.38 (s, 1H)

Example 1304-(2-methyltetrahydro-2H-pyran-4-yl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.95 g), sodium hydrogencarbonate (1.5 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[4-(2-methyltetrahydro-2H-pyran-4-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.43 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.18 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.23 g, 47%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H), 1.13-1.30 (m, 3H),1.44-1.75 (m, 4H), 2.34-2.47, 2.59-2.99 (m, combined 4H), 3.41-3.58,3.66-3.82 (m, combined 2H), 3.91-4.03, 4.22-4.31 (m, combined 3H),5.08-5.24, 5.36-5.51 (m, combined 1H), 7.17-7.25 (m, 2H), 7.27-7.36 (m,2H), 7.47-7.58 (m, 2H), 7.61-7.73 (m, 2H), 8.20 (s, 1H), 12.38 (br. s.,1H)

Example 1314-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-6-{1-[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]ethyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.75 g), sodium hydrogencarbonate (1.20 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-(1-{4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}ethyl)biphenyl-2-carbonitrile(0.39 g) was added, and the mixture was stirred at 90° C. for 15 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.20 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.20 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.16 g, 37%).

¹H NMR (300 MHz, CDCl₃) δ 1.12 (t, J=7.5 Hz, 3H), 1.18 (s, 6H),1.34-1.94 (m, 9H), 2.10-2.24 (m, 2H), 2.35 (s, 1H), 2.54-2.72 (m, 2H),3.00-3.20 (m, 2H), 3.28 (s, 2H), 3.34-3.48 (m, 1H), 4.36-4.48 (m, 1H),4.86-5.02 (m, 1H), 7.24-7.30 (m, 2H), 7.36-7.52 (m, 4H), 7.56-7.64 (m,1H), 7.84-7.88 (m, 1H), 7.90 (s, 1H)

Example 1327-butyl-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-(tetrahydro-2H-pyran-4-yl)[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.1 g), sodium hydrogencarbonate (1.8 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[7-butyl-2-methyl-5-oxo-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.52 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.21 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.18 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.31 g,52%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.21 (t, J=7.1 Hz, 3H), 0.64-1.05 (m, 6H),1.74 (s, 3H), 2.05-2.37 (m, 4H), 2.80 (t, J=11.6 Hz, 2H), 3.28-3.41 (m,4H), 4.43-4.59 (m, 1H), 6.55-6.63 (m, 2H), 6.64-6.72 (m, 2H), 6.81-6.97(m, 2H), 6.98-7.10 (m, 2H), 11.76 (s, 1H)

Example 1334-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.89 g), sodium hydrogencarbonate (1.4 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.41 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.17 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.25 g,54%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.4 Hz, 3H), 1.18 (s, 3H), 1.26(s, 3H), 1.46-1.65 (m, 4H), 2.52-2.62 (m, 1H), 2.65-2.83 (m, 1H),2.90-2.97 (m, 2H), 3.62-3.81 (m, 2H), 3.97 (s, 2H), 5.28-5.45 (m, 1H),7.18-7.25 (m, 2H), 7.26-7.37 (m, 2H), 7.53 (dd, J=16.1, 7.8 Hz, 2H),7.63-7.74 (m, 2H), 8.20 (s, 1H), 12.38 (s, 1H)

Example 1347-butyl-4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.95 g), sodium hydrogencarbonate (1.5 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[7-butyl-4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.45 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.18 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.21 g,42%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (t, J=7.2 Hz, 3H), 1.19 (s, 3H), 1.26(s, 3H), 1.28-1.41 (m, 2H), 1.40-1.64 (m, 4H), 2.52-2.61 (m, 1H),2.62-2.82 (m, 1H), 2.89-3.01 (m, 2H), 3.63-3.81 (m, 2H), 3.96 (s, 2H),5.31-5.47 (m, 1H), 7.19-7.26 (m, 2H), 7.28-7.35 (m, 2H), 7.46-7.59 (m,2H), 7.61-7.74 (m, 2H), 8.20 (s, 1H), 12.39 (s, 1H)

Example 1357-butyl-6-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-4-(tetrahydro-2H-pyran-4-yl)[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1 g), sodium hydrogen carbonate(1.7 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min,4′-{[7-butyl-2-methyl-5-oxo-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile(0.49 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.19 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.16 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.32 g,57%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (t, J=7.2 Hz, 3H), 1.26-1.42 (m, 2H),1.45-1.62 (m, 4H), 2.37 (s, 3H), 2.66-2.84 (m, 2H), 2.84-2.93 (m, 2H),3.42 (t, J=11.4 Hz, 2H), 3.89-4.00 (m, 4H), 5.02-5.18 (m, 1H), 6.98 (dd,J=8.0, 1.5 Hz, 1H), 7.13-7.28 (m, 2H), 7.49-7.62 (m, 2H), 7.63-7.75 (m,2H), 12.46 (s, 1H)

Example 1364-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-6-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.69 g), sodium hydrogencarbonate (1.1 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile(0.34 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.13 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.23 g,62%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.4 Hz, 3H), 1.18 (s, 3H), 1.24(s, 3H), 1.48-1.64 (m, 4H), 2.38 (s, 3H), 2.51-2.59 (m, 1H), 2.64-2.81(m, 1H), 2.83-2.93 (m, 2H), 3.61-3.79 (m, 2H), 3.92 (s, 2H), 5.20-5.41(m, 1H), 6.99 (dd, J=8.0, 1.5 Hz, 1H), 7.11-7.27 (m, 2H), 7.49-7.62 (m,2H), 7.64-7.77 (m, 2H), 12.45 (s, 1H)

Example 1377-butyl-4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.8 g), sodium hydrogencarbonate (1.3 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[7-butyl-4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-methyl-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.39 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.15 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.13 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.25 g,58%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (t, J=7.4 Hz, 3H), 1.18 (s, 3H), 1.25(s, 3H), 1.28-1.40 (m, 2H), 1.42-1.61 (m, 4H), 2.37 (s, 3H), 2.52-2.59(m, 1H), 2.65-2.81 (m, 1H), 2.84-2.95 (m, 2H), 3.62-3.80 (m, 2H), 3.93(s, 2H), 5.24-5.42 (m, 1H), 7.18-7.25 (m, 2H), 7.25-7.33 (m, 2H),7.45-7.59 (m, 2H), 7.61-7.74 (m, 2H), 12.38 (br. s., 1H)

Example 1387-butyl-4-[(2R,4s,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.2 g), sodium hydrogencarbonate (3.2 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-({7-butyl-4-[(2R,4s,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.094 g) was added, and the mixture was stirred at 90° C. for 16 hr.The reaction mixture was diluted with ethyl acetate, washed with waterand then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was dissolved in tetrahydrofuran (5 mL).N,N′-Carbonyldiimidazole (0.037 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.031 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.029g, 28%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (t, J=7.2 Hz, 3H), 1.07-1.17 (m, 6H),1.28-1.41 (m, 2H), 1.41-1.69 (m, 4H), 2.39-2.48 (m, 2H), 2.88-2.98 (m,2H), 3.98 (s, 2H), 4.09-4.22 (m, 2H), 5.22-5.35 (m, 1H), 7.20-7.25 (m,2H), 7.28-7.35 (m, 2H), 7.47-7.60 (m, 2H), 7.62-7.72 (m, 2H), 8.18 (s,1H), 12.39 (s, 1H)

Example 1397-butyl-4-[(2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.58 g), sodium hydrogencarbonate (0.93 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-({7-butyl-4-[(2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.27 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.11 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.092 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.2 g,66%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (t, J=7.2 Hz, 3H), 1.15 (d, J=6.1 Hz,6H), 1.28-1.41 (m, 2H), 1.42-1.54 (m, 2H), 1.60-1.72 (m, 2H), 2.36 (q,J=12.1 Hz, 2H), 2.90-2.99 (m, 2H), 3.48-3.62 (m, 2H), 3.96 (s, 2H),5.12-5.26 (m, 1H), 7.18-7.25 (m, 2H), 7.28-7.33 (m, 2H), 7.46-7.59 (m,2H), 7.61-7.74 (m, 2H), 8.19 (s, 1H), 12.39 (s, 1H)

Example 1404-(1,4-dioxaspiro[4.5]dec-8-yl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.82 g), sodium hydrogencarbonate (1.3 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.4 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.15 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.13 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.27 g,64%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H), 1.44-1.82 (m, 8H),2.68-2.84 (m, 2H), 2.86-2.98 (m, 2H), 3.82-3.99 (m, 6H), 4.88-5.03 (m,1H), 7.15-7.26 (m, 2H), 7.28-7.34 (m, 2H), 7.45-7.58 (m, 2H), 7.60-7.73(m, 2H), 8.19 (s, 1H), 12.38 (s, 1H)

Example 1417-butyl-4-(1,4-dioxaspiro[4.5]dec-8-yl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.79 g), sodium hydrogencarbonate (1.3 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[7-butyl-4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.4 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.15 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.13 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.32 g,72%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (t, J=7.2 Hz, 3H), 1.29-1.54 (m, 4H),1.56-1.70 (m, 4H), 1.71-1.83 (m, 2H), 2.70-2.88 (m, 2H), 2.90-2.99 (m,2H), 3.83-3.98 (m, 6H), 4.90-5.04 (m, 1H), 7.19-7.25 (m, 2H), 7.27-7.35(m, 2H), 7.46-7.58 (m, 2H), 7.61-7.72 (m, 2H), 8.19 (s, 1H), 12.39 (s,1H)

Example 1427-butyl-4-(4-oxocyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of7-butyl-4-(1,4-dioxaspiro[4.5]dec-8-yl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.27 g), 6N hydrochloric acid (2 mL) and tetrahydrofuran (10 mL) wasstirred at 40° C. for 3 hr. The reaction mixture was diluted with ethylacetate, washed with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (0.21 g, 83%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (t, J=7.2 Hz, 3H), 1.27-1.40 (m, 2H),1.43-1.55 (m, 2H), 1.96-2.06 (m, 2H), 2.32 (d, J=14.8 Hz, 2H), 2.58-2.75(m, 2H), 2.78-2.99 (m, 4H), 3.98 (s, 2H), 5.39-5.56 (m, 1H), 7.19-7.26(m, 2H), 7.28-7.36 (m, 2H), 7.45-7.59 (m, 2H), 7.62-7.72 (m, 2H), 8.19(s, 1H), 12.40 (s, 1H)

Example 1434-(4-oxocyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4-(1,4-dioxaspiro[4.5]dec-8-yl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.27 g), 6N hydrochloric acid (2 mL) and tetrahydrofuran (10 mL) wasstirred at 40° C. for 3 hr. The reaction mixture was diluted with ethylacetate, washed with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (0.2 g, 81%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.4 Hz, 3H), 1.48-1.62 (m, 2H),1.96-2.06 (m, 2H), 2.26-2.37 (m, 2H), 2.59-2.75 (m, 2H), 2.77-2.99 (m,4H), 3.98 (s, 2H), 5.40-5.55 (m, 1H), 7.16-7.25 (m, 2H), 7.28-7.36 (m,2H), 7.53 (dd, J=16.1, 7.8 Hz, 2H), 7.61-7.75 (m, 2H), 8.20 (s, 1H),12.39 (s, 1H)

Example 1442-methyl-4-(6-methyltetrahydro-2H-pyran-3-yl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.39 g), sodium hydrogencarbonate (0.64 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-{[2-methyl-4-(6-methyltetrahydro-2H-pyran-3-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.18 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.073 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.062 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.097 g, 47%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91 (t, J=7.3 Hz, 3H), 1.13 (d, J=6.2 Hz,3H), 1.30-1.59 (m, 3H), 1.72-1.87 (m, 2H), 2.35 (s, 3H), 2.69-2.92 (m,3H), 3.42-3.55 (m, 1H), 3.78 (dd, J=8.5, 2.3 Hz, 1H), 3.93 (s, 2H), 4.28(t, J=10.7 Hz, 1H), 4.86-5.00 (m, 1H), 7.18-7.25 (m, 2H), 7.26-7.32 (m,2H), 7.47-7.59 (m, 2H), 7.61-7.74 (m, 2H), 12.38 (br. s., 1H)

Example 1456-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-pentyl-4-(tetrahydro-2H-pyran-4-yl)[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1 g), sodium hydrogen carbonate(1.7 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min,4′-{[5-oxo-7-pentyl-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.48 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.19 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.16 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.37 g, 68%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.81 (t, J=7.0 Hz, 3H), 1.17-1.37 (m, 4H),1.45-1.64 (m, 4H), 2.67-2.84 (m, 2H), 2.87-2.98 (m, 2H), 3.43 (t, J=11.2Hz, 2H), 3.93-4.03 (m, 4H), 5.09-5.25 (m, 1H), 7.18-7.25 (m, 2H),7.28-7.34 (m, 2H), 7.44-7.59 (m, 2H), 7.62-7.74 (m, 2H), 8.20 (s, 1H),12.39 (s, 1H)

Example 1464-(4-hydroxycyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

To a solution (10 mL) of4-(4-oxocyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.14 g) in methanol was added sodium borohydride (0.011 g), and themixture was stirred at room temperature for 1 hr. After evaporation ofthe solvent under reduced pressure, the residue was extracted with waterand ethyl acetate. The obtained ethyl acetate layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.09 g, 66%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H), 1.21-1.99 (m, 8H),2.51-2.65 (m, 2H), 2.86-3.00 (m, 2H), 3.39-3.99 (m, 3H), 4.33-4.69 (m,1H), 4.79-4.96 (m, 1H), 7.18-7.25 (m, 2H), 7.27-7.34 (m, 2H), 7.46-7.59(m, 2H), 7.62-7.73 (m, 2H), 8.18 (s, 1H), 12.38 (s, 1H)

Example 1477-butyl-4-(4-hydroxycyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

To a mixture of7-butyl-4-(4-oxocyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.08 g), tetrahydrofuran (3 mL) and methanol (3 mL) was added sodiumborohydride (0.007 g), and the mixture was stirred at room temperaturefor 1 hr. After evaporation of the solvent under reduced pressure, theresidue was extracted with water and ethyl acetate. The obtained ethylacetate layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless amorphous solid (0.04 g, 48%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (t, J=7.2 Hz, 3H) 1.21-1.99 (m, 10H)2.52-2.62 (m, 2H) 2.88-3.00 (m, 2H) 3.39-3.56, 3.84-3.90 (m, combined0H) 3.95 (s, 2H) 4.34-4.68 (m, 1H) 4.80-4.94 (m, 1H) 7.18-7.34 (m, 4H)7.44-7.58 (m, 1H) 7.61-7.73 (m, 1H) 8.18 (s, 1H) 12.39 (s, 1H)

Example 1487-butyl-4-(4-methoxycyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.34 g), sodium hydrogencarbonate (0.54 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-{[7-butyl-4-(4-methoxycyclohexyl)-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.16 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.063 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.053 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.069 g, 39%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (t, J=6.9 Hz, 3H), 1.21-1.54 (m, 8H),1.65-1.76 (m, 2H), 2.06-2.18 (m, 2H), 2.90-2.99 (m, 2H), 3.13-3.28 (m,4H), 3.95 (s, 2H), 4.84-4.99 (m, 1H), 7.19-7.25 (m, 2H), 7.27-7.33 (m,2H), 7.46-7.58 (m, 2H), 7.62-7.72 (m, 2H), 8.16-8.20 (m, 1H), 12.38 (s,1H)

Example 1492-methyl-4-(5-methyltetrahydrofuran-3-yl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.22 g), sodium hydrogencarbonate (0.36 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-{[2-methyl-4-(5-methyltetrahydrofuran-3-yl)-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.1 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.042 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.035 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.076g, 67%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91 (t, J=7.3 Hz, 3H), 1.21 (d, J=6.0 Hz,3H), 1.45-1.61 (m, 2H), 1.66-1.82 (m, 1H), 2.36 (s, 3H), 2.42-2.56 (m,1H), 2.81-2.93 (m, 2H), 3.89-4.07 (m, 4H), 4.48-4.61 (m, 1H), 5.55-5.68(m, 1H), 7.19-7.25 (m, 2H), 7.27-7.33 (m, 2H), 7.47-7.58 (m, 2H),7.61-7.73 (m, 2H), 12.38 (s, 1H)

Example 1504-[(5S,8S)-1-oxaspiro[4.5]dec-8-yl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate(0.78 g) and N-(1-oxaspiro[4.5]dec-8-yl)-4H-1,2,4-triazol-3-amine (0.25g) was stirred under microwave irradiation at 250° C. for 20 min. Thereaction mixture was purified by silica gel column chromatography, theobtained residue was dissolved in dimethyl sulfoxide (5 mL), and themixture was added to a mixture of hydroxylammonium chloride (0.55 g),sodium hydrogen carbonate (0.89 g) and dimethyl sulfoxide (5 mL), whichhad been stirred in advance at 40° C. for 30 min. The reaction mixturewas stirred at 90° C. for 16 hr, diluted with ethyl acetate, washed withwater and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography, and dissolvedin tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.1 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.088 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.055g, 9%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.4 Hz, 3H), 1.40-1.77 (m, 10H),1.80-1.91 (m, 2H), 2.71-3.00 (m, 4H), 3.75 (t, J=6.6 Hz, 2H), 3.96 (s,2H), 4.82-4.97 (m, 1H), 7.17-7.25 (m, 2H), 7.28-7.34 (m, 2H), 7.47-7.58(m, 2H), 7.61-7.73 (m, 2H), 8.19 (s, 1H), 12.38 (s, 1H)

Example 1514-[(5R,8R)-1-oxaspiro[4.5]dec-8-yl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate(0.78 g) and N-(1-oxaspiro[4.5]dec-8-yl)-4H-1,2,4-triazol-3-amine (0.25g) was stirred under microwave irradiation at 250° C. for 20 min. Thereaction mixture was purified by silica gel column chromatography, theobtained residue was dissolved in dimethyl sulfoxide (5 mL), and themixture was added to a mixture of hydroxylammonium chloride (0.55 g),sodium hydrogen carbonate (0.89 g) and dimethyl sulfoxide (5 mL), whichhad been stirred in advance at 40° C. for 30 min. The reaction mixturewas stirred at 90° C. for 16 hr, diluted with ethyl acetate, washed withwater and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography, and dissolvedin tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.1 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.088 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.058g, 9%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.4 Hz, 3H), 1.43-1.74 (m, 8H),1.79-1.94 (m, 4H), 2.53-2.69 (m, 2H), 2.88-2.97 (m, 2H), 3.72 (t, J=6.2Hz, 2H), 3.96 (s, 2H), 4.83-5.02 (m, 1H), 7.18-7.25 (m, 2H), 7.27-7.36(m, 2H), 7.53 (dd, J=16.7, 7.6 Hz, 2H), 7.61-7.75 (m, 2H), 8.20 (s, 1H),12.38 (s, 1H)

Example 1524-(4-methoxycyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.38 g), sodium hydrogencarbonate (0.61 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[4-(4-methoxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.21 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.07 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.059 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.049 g, 25%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H), 1.12-1.76 (m, 6H),1.90-2.20 (m, 3H), 2.54-2.97 (m, 4H), 3.19-3.27 (m, 3H), 3.96 (s, 2H),4.80-4.98 (m, 1H), 7.19-7.23 (m, 2H), 7.27-7.34 (m, 2H), 7.46-7.58 (m,2H), 7.61-7.72 (m, 2H), 8.19 (s, 1H), 12.37 (s, 1H)

Example 1536-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[4-(prop-2-en-1-yloxy)cyclohexyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.41 g), sodium hydrogencarbonate (0.66 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-({5-oxo-4-[4-(prop-2-en-1-yloxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.2 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.077 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.065 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.13 g, 56%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H) 1.22-1.61 (m, 6H)1.63-1.75 (m, 1H) 1.93-2.16 (m, 2H) 2.52-2.97 (m, 4H) 3.91-4.03 (m, 4H)4.84-5.00 (m, 1H) 5.08-5.18 (m, 1H) 5.21-5.40 (m, 1H) 5.80-6.01 (m, 1H)7.19-7.25 (m, 2H) 7.26-7.35 (m, 2H) 7.46-7.59 (m, 2H) 7.61-7.72 (m, 2H)8.14-8.21 (m, 1H) 12.38 (s, 1H)

Example 1544-[4-(2-methoxyethoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.15 g), sodium hydrogencarbonate (0.25 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-({4-[4-(2-methoxyethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.078 g) was added, and the mixture was stirred at 90° C. for 16 hr.The reaction mixture was diluted with ethyl acetate, washed with waterand then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was dissolved in tetrahydrofuran (10 mL).N,N′-Carbonyldiimidazole (0.029 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.024 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.04 g, 46%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.2 Hz, 3H), 1.17-1.74 (m, 6H),1.92-2.15 (m, 2H), 2.52-2.85 (m, 2H), 2.89-2.98 (m, 2H), 3.24 (s, 3H),3.38-3.45 (m, 1H), 3.47-3.59 (m, 4H), 3.96 (s, 2H), 4.84-4.98 (m, 1H),7.18-7.34 (m, 4H), 7.53 (dd, J=16.5, 7.8 Hz, 2H), 7.61-7.72 (m, 2H),8.18 (s, 1H), 12.37 (br. s., 1H)

Example 1554-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-2-methyl-6-{[2-methyl-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.75 g), sodium hydrogencarbonate (1.21 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)-2′-methylbiphenyl-2-carbonitrile(0.41 g) was added, and the mixture was stirred at 90° C. for 15 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.20 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.20 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.26 g, 58%).

¹H NMR (300 MHz, CDCl₃) δ 1.08 (t, J=7.2 Hz, 3H), 1.20 (s, 6H),1.36-1.85 (m, 6H), 2.01 (s, 3H), 2.10-2.24 (m, 2H), 2.43 (s, 3H),2.60-2.80 (m, 2H), 2.96-3.10 (m, 2H), 3.31 (s, 2H), 3.38-3.52 (m, 1H),3.94 (s, 2H), 4.92-5.06 (m, 1H), 7.06-7.30 (m, 4H), 7.46-7.64 (m, 2H),7.98-8.06 (m, 1H)

Example 1564-(4-morpholin-4-ylcyclohexyl)-7-propyl-6-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4′-{[4-(4-morpholin-4-ylcyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.08 g), dibutyltin oxide (0.0037 g), azidotrimethylsilane (0.26 g) andtoluene (10 mL) was stirred at 110° C. for 48 hr. The reaction mixturewas diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.02 g, 23%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (t, J=7.1 Hz, 3H), 1.36-1.61 (m, 6H),2.06-2.17 (m, 3H), 2.41-2.60 (m, 4H), 2.68-2.93 (m, 4H), 3.69 (br. s.,4H), 3.91 (s, 2H), 4.86-4.99 (m, 1H), 6.99 (d, J=8.1 Hz, 2H), 7.17 (d,J=8.1 Hz, 2H), 7.53 (dd, J=13.6, 7.3 Hz, 2H), 7.58-7.68 (m, 2H), 8.19(s, 1H)

Example 1574-(4-morpholin-4-ylcyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.23 g), sodium hydrogencarbonate (0.38 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[4-(4-morpholin-4-ylcyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.12 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.043 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.037 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was poured into water, and the mixture was adjusted to pH 7 with1 N hydrochloric acid and extracted with ethyl acetate. The obtainedethyl acetate layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.025 g, 20%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H), 1.31-1.59 (m, 6H),2.03-2.20 (m, 3H), 2.42 (br. s., 4H), 2.71-2.96 (m, 4H), 3.61-3.69 (m,4H), 3.96 (s, 2H), 4.86-5.01 (m, 1H), 7.19-7.26 (m, 2H), 7.27-7.33 (m,2H), 7.46-7.58 (m, 2H), 7.60-7.72 (m, 2H), 8.18 (s, 1H), 12.32 (br. s.,1H)

Example 1584-[cis-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.26 g), sodium hydrogencarbonate (0.42 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-({4-[4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.14 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.049 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.041 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.069g, 46%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.2 Hz, 3H), 1.18 (s, 6H),1.37-1.60 (m, 6H), 1.93-2.08 (m, 2H), 2.74-2.97 (m, 4H), 3.15 (s, 2H),3.96 (s, 2H), 4.23 (s, 1H), 4.85-5.04 (m, 1H), 7.17-7.26 (m, 2H),7.27-7.34 (m, 2H), 7.53 (dd, J=16.1, 7.6 Hz, 2H), 7.62-7.71 (m, 2H),8.14 (s, 1H), 12.38 (br. s., 1H)

Example 1597-butyl-4-(2-methyltetrahydro-2H-pyran-4-yl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.33 g), sodium hydrogencarbonate (0.53 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[7-butyl-4-(2-methyltetrahydro-2H-pyran-4-yl)-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(tR1, 0.15 g) obtained in Reference Example 113 was added, and themixture was stirred at 90° C. for 16 hr. The reaction mixture wasdiluted with ethyl acetate, washed with water and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was dissolved intetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.061 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.052 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.061g, 36%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (t, J=7.3 Hz, 3H) 1.10-1.72 (m, 9H)2.34-2.47 (m, 1H) 2.63-2.78 (m, 1H) 2.90-3.00 (m, 2H) 3.41-3.56 (m, 2H)3.92-4.05 (m, 3H) 5.10-5.26 (m, 1H) 7.19-7.34 (m, 4H) 7.47-7.59 (m, 2H)7.63-7.73 (m, 2H) 8.20 (s, 1H) 12.39 (s, 1H)

Example 1607-butyl-4-(2-methyltetrahydro-2H-pyran-4-yl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.13 g), sodium hydrogencarbonate (0.21 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-{[7-butyl-4-(2-methyltetrahydro-2H-pyran-4-yl)-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(tR2, 0.057 g) obtained in Reference Example 113 was added, and themixture was stirred at 90° C. for 16 hr. The reaction mixture wasdiluted with ethyl acetate, washed with water and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was dissolved intetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.024 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.02 mL) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.026g, 39%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (t, J=7.2 Hz, 3H) 1.22-1.67 (m, 9H)2.69-3.03 (m, 4H) 3.64-3.84 (m, 2H) 3.96 (s, 2H) 4.19-4.34 (m, 1H)5.34-5.50 (m, 1H) 7.17-7.36 (m, 4H) 7.45-7.60 (m, 2H) 7.61-7.73 (m, 2H)8.20 (s, 1H) 12.39 (s, 1H)

Example 1617-butyl-4-(2-methyltetrahydro-2H-pyran-4-yl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.32 g), sodium hydrogencarbonate (0.51 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[7-butyl-4-(2-methyltetrahydro-2H-pyran-4-yl)-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(tR3, 0.14 g) obtained in Reference Example 113 was added, and themixture was stirred at 90° C. for 16 hr. The reaction mixture wasdiluted with ethyl acetate, washed with water and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was dissolved intetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.059 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.05 mL) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.043g, 26%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (t, J=7.2 Hz, 3H) 1.08-1.74 (m, 9H)2.35-2.47 (m, 1H) 2.59-2.78 (m, 1H) 2.89-3.01 (m, 2H) 3.42-3.59 (m, 2H)3.89-4.03 (m, 3H) 5.10-5.25 (m, 1H) 7.18-7.35 (m, 4H) 7.46-7.59 (m, 2H)7.61-7.73 (m, 2H) 8.20 (s, 1H) 12.39 (s, 1H)

Example 1627-butyl-4-(2-methyltetrahydro-2H-pyran-4-yl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.13 g), sodium hydrogencarbonate (0.21 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-{[7-butyl-4-(2-methyltetrahydro-2H-pyran-4-yl)-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(tR4, 0.14 g) obtained in Reference Example 113 was added, and themixture was stirred at 90° C. for 16 hr. The reaction mixture wasdiluted with ethyl acetate, washed with water and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was dissolved intetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.024 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.02 mL) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.029g, 43%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (t, J=7.2 Hz, 3H) 1.23-1.66 (m, 9H)2.68-3.01 (m, 4H) 3.67-3.83 (m, 2H) 3.96 (s, 2H) 4.20-4.35 (m, 1H)5.34-5.51 (m, 1H) 7.19-7.34 (m, 4H) 7.47-7.59 (m, 2H) 7.61-7.73 (m, 2H)8.20 (s, 1H) 12.39 (s, 1H)

Example 1634-[cis-4-(2-hydroxyethoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4′-({4-[cis-4-(2-hydroxyethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.29 g), tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.19 mL),2,6-lutidine (0.099 mL) and tetrahydrofuran (10 mL) was stirred at 0° C.for 3 hr. The reaction mixture was diluted with ethyl acetate, washedwith water and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The residue obtained by silica gel column chromatography was dissolvedin dimethyl sulfoxide (5 mL), and added to a mixture of hydroxylammoniumchloride (0.59 g), sodium hydrogen carbonate (0.95 g) and dimethylsulfoxide (5 mL), which had been stirred in advance at 40° C. for 30min. The reaction mixture was stirred at 90° C. for 16 hr, diluted withethyl acetate, washed with water and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was dissolved in tetrahydrofuran (10mL). N,N′-Carbonyldiimidazole (0.11 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.093 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was dissolved in tetrahydrofuran (15 mL).Tetrabutylammonium bromide (1.0 M tetrahydrofuran solution, 1.4 mL) wasadded, and the mixture was stirred at room temperature for 3 hr. Thereaction mixture was extracted with 1 N hydrochloric acid and ethylacetate, and the ethyl acetate layer was washed with saturated brine andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.11 g, 34%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H), 1.36-1.60 (m, 6H),1.93-2.04 (m, 2H), 2.69-2.99 (m, 4H), 3.37-3.47 (m, 2H), 3.50-3.60 (m,3H), 3.96 (s, 2H), 4.53 (t, J=5.5 Hz, 1H), 4.83-5.00 (m, 1H), 7.18-7.26(m, 2H), 7.27-7.35 (m, 2H), 7.47-7.60 (m, 2H), 7.62-7.72 (m, 2H), 8.18(s, 1H), 12.38 (s, 1H)

Example 1644-[trans-4-(2-hydroxyethoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4′-({4-[trans-4-(2-hydroxyethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.23 g), tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.16 mL),2,6-lutidine (0.079 mL) and tetrahydrofuran (10 mL) was stirred at 0° C.for 3 hr. The reaction mixture was diluted with ethyl acetate, washedwith water and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The residue obtained by silica gel column chromatography was dissolvedin dimethyl sulfoxide (5 mL), and the mixture was added to a mixture ofhydroxylammonium chloride (0.47 g), sodium hydrogen carbonate (0.76 g)and dimethyl sulfoxide (5 mL), which had been stirred in advance at 40°C. for 30 min. The reaction mixture was stirred at 90° C. for 16 hr,diluted with ethyl acetate, washed with water and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was dissolved intetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.088 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.074 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was dissolved in tetrahydrofuran (10 mL).Tetrabutylammonium bromide (1.0 M tetrahydrofuran solution, 1.1 mL) wasadded, and the mixture was stirred at room temperature for 3 hr. Thereaction mixture was extracted with 1 N hydrochloric acid and ethylacetate, and the ethyl acetate layer was washed with saturated brine andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.12 g, 45%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H), 1.19-1.37 (m, 3H),1.46-1.60 (m, 2H), 1.64-1.75 (m, 2H), 2.05-2.17 (m, 2H), 2.54-2.65 (m,2H), 2.88-2.97 (m, 2H), 3.41-3.51 (m, 4H), 3.96 (s, 2H), 4.51-4.60 (m,1H), 4.85-4.97 (m, 1H), 7.18-7.25 (m, 2H), 7.27-7.33 (m, 2H), 7.46-7.59(m, 2H), 7.61-7.72 (m, 2H), 8.18 (s, 1H), 12.38 (s, 1H)

Example 1654-[4-hydroxy-4-(2-hydroxyethyl)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4′-({4-[4-hydroxy-4-(2-hydroxyethyl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.093 g), tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.063mL), 2,6-lutidine (0.032 mL) and tetrahydrofuran (5 mL) was stirred at0° C. for 3 hr. The reaction mixture was diluted with ethyl acetate,washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The residue obtained by silica gel column chromatography wasdissolved in dimethyl sulfoxide (5 mL), and the mixture was added to amixture of hydroxylammonium chloride (0.19 g), sodium hydrogen carbonate(0.31 g) and dimethyl sulfoxide (5 mL), which had been stirred inadvance at 40° C. for 30 min. The reaction mixture was stirred at 90° C.for 16 hr, diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was dissolved intetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.035 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.03 mL) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was dissolved in tetrahydrofuran (10 mL).Tetrabutylammonium bromide (1.0 M tetrahydrofuran solution, 0.46 mL) wasadded, and the mixture was stirred at room temperature for 3 hr. Thereaction mixture was extracted with 1 N hydrochloric acid and ethylacetate, and the ethyl acetate layer was washed with saturated brine andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.024 g, 23%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.2 Hz, 3H), 1.38-1.60 (m, 6H),1.72-1.90 (m, 4H), 2.58-2.76 (m, 2H), 2.88-2.97 (m, 2H), 3.56-3.65 (m,2H), 3.96 (s, 2H), 4.40-4.46 (m, 2H), 4.81-4.99 (m, 1H), 7.18-7.26 (m,2H), 7.28-7.32 (m, 2H), 7.47-7.60 (m, 2H), 7.62-7.71 (m, 2H), 8.21 (s,1H), 12.38 (br. s., 1H)

Example 1666-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-(cis-4-hydroxycyclohexyl)-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of3′-fluoro-4′-{[4-(cis-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.085 g), tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.06mL), 2,6-lutidine (0.03 mL) and tetrahydrofuran (5 mL) was stirred at 0°C. for 3 hr. The reaction mixture was diluted with ethyl acetate, washedwith water and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The residue obtained by silica gel column chromatography was dissolvedin dimethyl sulfoxide (5 mL), and the mixture was added to a mixture ofhydroxylammonium chloride (0.18 g), sodium hydrogen carbonate (0.29 g)and dimethyl sulfoxide (5 mL), which had been stirred in advance at 40°C. for 30 min. The reaction mixture was stirred at 90° C. for 16 hr,diluted with ethyl acetate, washed with water and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was dissolved intetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.034 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.029 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was dissolved in tetrahydrofuran (10 mL).Tetrabutylammonium bromide (1.0 M tetrahydrofuran solution, 0.44 mL) wasadded, and the mixture was stirred at room temperature for 3 hr. Thereaction mixture was extracted with 1 N hydrochloric acid and ethylacetate, and the ethyl acetate layer was washed with saturated brine andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.036 g, 38%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H), 1.31-1.41 (m, 2H),1.43-1.63 (m, 4H), 1.72-1.82 (m, 2H), 2.83-2.98 (m, 4H), 3.86 (br. s.,1H), 3.94 (s, 2H), 4.37 (d, J=2.1 Hz, 1H), 4.79-4.94 (m, 1H), 6.99 (dd,J=8.0, 1.8 Hz, 1H), 7.16 (dd, J=11.1, 1.7 Hz, 1H), 7.20-7.29 (m, 1H),7.49-7.61 (m, 2H), 7.64-7.74 (m, 2H), 8.19 (s, 1H), 12.46 (br. s., 1H)

Example 1676-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-(trans-4-hydroxycyclohexyl)-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of3′-fluoro-4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.27 g), tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.19 mL),2,6-lutidine (0.1 mL) and tetrahydrofuran (10 mL) was stirred at 0° C.for 3 hr. The reaction mixture was diluted with ethyl acetate, washedwith water and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The residue obtained by silica gel column chromatography was dissolvedin dimethyl sulfoxide (5 mL), and the mixture was added to a mixture ofhydroxylammonium chloride (0.59 g), sodium hydrogen carbonate (0.95 g)and dimethyl sulfoxide (5 mL), which had been stirred in advance at 40°C. for 30 min. The reaction mixture was stirred at 90° C. for 16 hr,diluted with ethyl acetate, washed with water and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was dissolved intetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.11 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.093 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was dissolved in tetrahydrofuran (15 mL).Tetrabutylammonium bromide (1.0 M tetrahydrofuran solution, 1.4 mL) wasadded, and the mixture was stirred at room temperature for 3 hr. Thereaction mixture was extracted with 1 N hydrochloric acid and ethylacetate, and the ethyl acetate layer was washed with saturated brine andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.12 g, 40%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H), 1.21-1.37 (m, 2H),1.48-1.69 (m, 4H), 1.87-1.97 (m, 2H), 2.51-2.62 (m, 2H), 2.88-2.97 (m,2H), 3.38-3.52 (m, 1H), 3.94 (s, 2H), 4.65 (d, J=4.3 Hz, 1H), 4.77-4.91(m, 1H), 6.99 (dd, J=7.9, 1.7 Hz, 1H), 7.16 (dd, J=11.1, 1.7 Hz, 1H),7.24 (t, J=8.0 Hz, 1H), 7.50-7.62 (m, 2H), 7.64-7.74 (m, 2H), 8.19 (s,1H), 12.46 (s, 1H)

Example 168 ethyltrans-4-[5-oxo-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl]cyclohexanecarboxylate

A mixture of hydroxylammonium chloride (0.16 g), sodium hydrogencarbonate (0.26 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min, ethyltrans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexanoate(0.08 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.03 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.025 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.033 g, 37%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H) 1.19 (t, J=7.1 Hz,3H) 1.41-1.60 (m, 5H) 1.68-1.78 (m, 2H) 1.99-2.10 (m, 2H) 2.24-2.38 (m,2H) 2.88-2.97 (m, 2H) 3.96 (s, 2H) 4.02-4.12 (m, 2H) 4.82-4.97 (m, 1H)7.18-7.24 (m, 2H) 7.26-7.34 (m, 2H) 7.53 (dd, J=16.6, 7.7 Hz, 2H)7.61-7.73 (m, 2H) 8.19 (s, 1H) 12.38 (br. s., 1H)

Example 1694-[trans-4-(3-methyl-1,2,4-oxadiazol-5-yl)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.3 g), sodium hydrogencarbonate (0.49 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-({4-[trans-4-(3-methyl-1,2,4-oxadiazol-5-yl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.16 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.057 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.048 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.066 g, 38%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.2 Hz, 3H), 1.47-1.76 (m, 4H),1.78-1.86 (m, 2H), 2.18-2.28 (m, 2H), 2.32 (s, 3H), 2.61-2.78 (m, 2H),2.89-3.11 (m, 3H), 3.97 (s, 2H), 4.92-5.06 (m, 1H), 7.18-7.25 (m, 2H),7.29-7.35 (m, 2H), 7.53 (dd, J=16.1, 7.8 Hz, 2H), 7.61-7.73 (m, 2H),8.20 (s, 1H), 12.38 (s, 1H)

Example 1704-(3,3-dimethyl-1,5-dioxaspiro[5.5]undec-9-yl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.66 g), sodium hydrogencarbonate (1.1 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[4-(3,3-dimethyl-1,5-dioxaspiro[5.5]undec-9-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.35 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.12 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.13 g,34%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.85-0.97 (m, 9H), 1.30-1.45 (m, 2H),1.47-1.60 (m, 4H), 2.28-2.39 (m, 2H), 2.61-2.78 (m, 2H), 2.87-2.99 (m,2H), 3.47 (d, J=8.3 Hz, 4H), 3.95 (s, 2H), 4.88-5.01 (m, 1H), 7.18-7.25(m, 2H), 7.27-7.35 (m, 2H), 7.53 (dd, J=16.7, 7.6 Hz, 2H), 7.60-7.73 (m,2H), 8.19 (s, 1H), 12.38 (br. s., 1H)

Example 1714-{trans-4-[2-(1H-imidazol-1-yl)ethoxy]cyclohexyl}-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.44 g), sodium hydrogencarbonate (0.71 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-[(4-{trans-4-[2-(1H-imidazol-1-yl)ethoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.24 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.083 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.07 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was poured into water, and the mixture was adjusted to pH 7 with1 N hydrochloric acid and extracted with ethyl acetate. The obtainedethyl acetate layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.086g, 33%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H), 1.15-1.33 (m, 2H),1.47-1.58 (m, 2H), 1.63-1.72 (m, 2H), 1.99-2.12 (m, 2H), 2.51-2.64 (m,2H), 2.87-2.98 (m, 2H), 3.23-3.38 (m, 1H), 3.72 (t, J=5.2 Hz, 2H), 3.95(s, 2H), 4.11 (t, J=5.1 Hz, 2H), 4.82-4.95 (m, 1H), 6.92 (br. s., 1H),7.15-7.25 (m, 3H), 7.26-7.33 (m, 2H), 7.45-7.58 (m, 2H), 7.60-7.81 (m,3H), 8.17 (s, 1H), 12.52 (br. s., 1H)

Example 1724-[trans-4-(2-morpholin-4-ylethoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.54 g), sodium hydrogencarbonate (0.87 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-({4-[trans-4-(2-morpholin-4-ylethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.3 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.1 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.085 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was poured into water, and the mixture was adjusted to pH 7 with1 N hydrochloric acid and extracted with ethyl acetate. The obtainedethyl acetate layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.2 g,59%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.2 Hz, 3H), 1.19-1.36 (m, 2H),1.47-1.61 (m, 2H), 1.64-1.75 (m, 2H), 2.04-2.16 (m, 2H), 2.43-2.67 (m,8H), 2.88-2.99 (m, 2H), 3.25-3.38 (m, 1H), 3.53-3.60 (m, 6H), 3.95 (s,2H), 4.83-4.96 (m, 1H), 7.18-7.24 (m, 2H), 7.27-7.33 (m, 2H), 7.45-7.57(m, 2H), 7.62-7.71 (m, 2H), 8.18 (s, 1H), 12.09 (br. s., 1H)

Example 1734-[trans-4-(5-methyl-1,3,4-oxadiazol-2-yl)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.35 g), sodium hydrogencarbonate (0.57 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-({4-[trans-4-(5-methyl-1,3,4-oxadiazol-2-yl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.18 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.066 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.056 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.083g, 42%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H), 1.49-1.87 (m, 6H),2.15-2.27 (m, 2H), 2.47 (s, 3H), 2.60-2.79 (m, 2H), 2.87-3.01 (m, 3H),3.97 (s, 2H), 4.90-5.05 (m, 1H), 7.20-7.26 (m, 2H), 7.29-7.35 (m, 2H),7.53 (dd, J=16.0, 7.7 Hz, 2H), 7.61-7.73 (m, 2H), 8.20 (s, 1H), 12.38(s, 1H)

Example 1744-[trans-4-(5-methyl-1,3,4-oxadiazol-2-yl)cyclohexyl]-7-propyl-6-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4′-({4-[trans-4-(5-methyl-1,3,4-oxadiazol-2-yl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.15 g), dibutyltin oxide (0.035 g), azidotrimethylsilane (0.97 g) andtoluene (15 mL) was stirred at 110° C. for 48 hr. The reaction mixturewas diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as colorlesscrystals (0.023 g, 14%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H), 1.46-1.86 (m, 6H),2.14-2.26 (m, 2H), 2.47 (s, 3H), 2.59-2.76 (m, 2H), 2.85-3.00 (m, 3H),3.91 (s, 2H), 4.91-5.03 (m, 1H), 6.99 (d, J=8.3 Hz, 2H), 7.19 (d, J=8.3Hz, 2H), 7.49-7.70 (m, 4H), 8.20 (s, 1H)

Example 1754-{trans-4-[(4-methoxyphenyl)carbonyl]cyclohexyl}-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.88 g), sodium hydrogencarbonate (1.4 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-[(4-{trans-4-[(4-methoxyphenyl)carbonyl]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.5 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue obtainedby silica gel column chromatography was dissolved in tetrahydrofuran (10mL). N,N′-Carbonyldiimidazole (0.16 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. 25% Sulfuric acid (5 mL) and ethanol (15 mL) were added to theobtained residue, and the mixture was stirred at 100° C. for 16 hr. Theprecipitated solid was collected by filtration to give the titlecompound as a colorless amorphous solid (0.24 g, 44%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.3 Hz, 3H), 1.48-1.62 (m, 4H),1.73-1.83 (m, 2H), 1.91-2.01 (m, 2H), 2.66-2.83 (m, 2H), 2.89-2.98 (m,2H), 3.36-3.49 (m, 1H), 3.86 (s, 3H), 3.97 (s, 2H), 4.87-5.02 (m, 1H),7.05 (d, J=9.0 Hz, 2H), 7.19-7.26 (m, 2H), 7.28-7.36 (m, 2H), 7.53 (dd,J=15.5, 7.8 Hz, 2H), 7.61-7.73 (m, 2H), 8.01 (d, J=8.9 Hz, 2H), 8.22 (s,1H), 12.38 (s, 1H)

Example 176trans-4-[5-oxo-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl]cyclohexanecarboxamide

A mixture of hydroxylammonium chloride (0.71 g), sodium hydrogencarbonate (1.1 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexanecarboxamide(0.34 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.13 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.31 g,82%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 0.93 (t, J=7.4 Hz, 3H), 1.40-1.60 (m,4H), 1.66-1.77 (m, 2H), 1.85-1.94 (m, 2H), 2.10-2.24 (m, 1H), 2.53-2.65(m, 2H), 2.87-2.97 (m, 2H), 3.96 (s, 2H), 4.83-4.99 (m, 1H), 6.73 (s,1H), 7.18-7.26 (m, 3H), 7.28-7.35 (m, 2H), 7.53 (dd, J=16.1, 7.8 Hz,2H), 7.61-7.72 (m, 2H), 8.18 (s, 1H)

Example 177trans-4-[5-oxo-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl]cyclohexanecarbonitrile

To a solution (10 mL) oftrans-4-[5-oxo-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl]cyclohexanecarboxamide(0.31 g) and pyridine (0.18 mL) in tetrahydrofuran was addedtrifluoroacetic acid anhydride (0.15 mL) at 0° C., and the mixture wasstirred for 30 min. The reaction mixture was diluted with ethyl acetate,washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.18 g,60%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H), 1.46-1.81 (m, 6H),2.09-2.22 (m, 2H), 2.52-2.62 (m, 2H), 2.74 (t, J=12.1 Hz, 1H), 2.87-2.98(m, 2H), 3.96 (s, 2H), 4.93 (t, J=12.0 Hz, 1H), 7.19-7.25 (m, 2H),7.27-7.34 (m, 2H), 7.45-7.59 (m, 2H), 7.62-7.74 (m, 2H), 8.18 (s, 1H),12.38 (br. s., 1H)

Example 1784-(trans-4-{2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]ethoxy}cyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.51 g), sodium hydrogencarbonate (0.82 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[4-(trans-4-{2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]ethoxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.3 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.095 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.081 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was poured into water, and the mixture was adjusted to pH 7 with1 N hydrochloric acid and extracted with ethyl acetate. The obtainedethyl acetate layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.19 g,59%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H), 1.03 (d, J=6.2 Hz,6H), 1.21-1.35 (m, 2H), 1.47-1.61 (m, 2H), 1.65-1.80 (m, 5H), 2.05-2.14(m, 2H), 2.51-2.66 (m, 2H), 2.79 (d, J=10.4 Hz, 2H), 2.87-2.97 (m, 2H),3.24-3.39 (m, 1H), 3.49-3.64 (m, 5H), 3.95 (s, 2H), 4.82-4.96 (m, 1H),7.17-7.26 (m, 2H), 7.26-7.33 (m, 2H), 7.44-7.58 (m, 2H), 7.61-7.70 (m,2H), 8.18 (s, 1H)

Example 1794-(2,2-dimethyl-1,4-dioxaspiro[4.5]dec-8-yl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.39 g), sodium hydrogencarbonate (0.63 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[4-(2,2-dimethyl-1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.2 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.072 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.061 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.1 g, 47%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H), 1.21-1.30 (m, 6H),1.46-1.70 (m, 6H), 1.74-1.86 (m, 2H), 2.71-2.86 (m, 2H), 2.88-2.98 (m,2H), 3.69-3.75 (m, 2H), 3.96 (s, 2H), 4.86-5.02 (m, 1H), 7.19-7.25 (m,2H), 7.28-7.36 (m, 2H), 7.46-7.58 (m, 2H), 7.62-7.72 (m, 2H), 8.17-8.21(m, 1H), 12.38 (br. s., 1H)

Example 1806-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl-4-(2,2,3,3-tetramethyl-1,4-dioxaspiro[4.5]dec-8-yl)[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.28 g), sodium hydrogencarbonate (0.45 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[5-oxo-7-propyl-4-(2,2,3,3-tetramethyl-1,4-dioxaspiro[4.5]dec-8-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.15 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.052 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.044 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.068g, 41%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.4 Hz, 3H), 1.17 (s, 6H), 1.21(s, 6H), 1.47-1.72 (m, 6H), 1.78-1.88 (m, 2H), 2.70-2.98 (m, 4H), 3.95(s, 2H), 4.84-4.97 (m, 1H), 7.19-7.25 (m, 2H), 7.28-7.34 (m, 2H), 7.53(dd, J=16.5, 7.4 Hz, 2H), 7.61-7.72 (m, 2H), 8.20 (s, 1H), 12.37 (s, 1H)

Example 1817-propyl-4-(2,2,3,3-tetramethyl-1,4-dioxaspiro[4.5]dec-8-yl)-6-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4′-{[5-oxo-7-propyl-4-(2,2,3,3-tetramethyl-1,4-dioxaspiro[4.5]dec-8-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.2 g), dibutyltin oxide (0.026 g), azidotrimethylsilane (1.2 g) andtoluene (15 mL) was stirred at 110° C. for 48 hr. The reaction mixturewas diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as colorlesscrystals (0.06 g, 28%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.4 Hz, 3H), 1.16 (s, 6H), 1.21(s, 6H), 1.46-1.70 (m, 6H), 1.78-1.88 (m, 2H), 2.69-2.94 (m, 4H), 3.89(s, 2H), 4.89 (t, J=12.7 Hz, 1H), 6.99 (d, J=8.3 Hz, 2H), 7.18 (d, J=8.0Hz, 2H), 7.53 (dd, J=13.3, 7.2 Hz, 2H), 7.59-7.71 (m, 2H), 8.19 (s, 1H),16.26 (br. s., 1H)

Example 1824-[cis-4-(2-hydroxyethoxy)-4-methylcyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4′-({4-[cis-4-(2-hydroxyethoxy)-4-methylcyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.36 g), tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.24 mL),2,6-lutidine (0.12 mL) and tetrahydrofuran (5 mL) was stirred at 0° C.for 3 hr. The reaction mixture was diluted with ethyl acetate, washedwith water and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The residue obtained by silica gel column chromatography was dissolvedin dimethyl sulfoxide (5 mL), and the mixture was added to a mixture ofhydroxylammonium chloride (0.72 g), sodium hydrogen carbonate (1.2 g)and dimethyl sulfoxide (5 mL), which had been stirred in advance at 40°C. for 30 min. The reaction mixture was stirred at 90° C. for 16 hr,diluted with ethyl acetate, washed with water and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was dissolved intetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.13 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was dissolved in tetrahydrofuran (10 mL).Tetrabutylammonium bromide (1.0 M tetrahydrofuran solution, 1.7 mL) wasadded, and the mixture was stirred at room temperature for 3 hr. Thereaction mixture was extracted with 1 N hydrochloric acid and ethylacetate, and the ethyl acetate layer was washed with saturated brine andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.11 g, 27%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.4 Hz, 3H), 1.12 (s, 3H),1.33-1.64 (m, 6H), 1.82-1.92 (m, 2H), 2.72-2.97 (m, 4H), 3.32-3.37 (m,2H), 3.53-3.64 (m, 2H), 3.96 (s, 2H), 4.43 (t, J=6.1 Hz, 1H), 4.86-5.00(m, 1H), 7.18-7.24 (m, 2H), 7.28-7.35 (m, 2H), 7.53 (dd, J=16.1, 7.8 Hz,2H), 7.62-7.72 (m, 2H), 8.16 (s, 1H), 12.37 (s, 1H)

Example 1834-[trans-4-(2-hydroxyethoxy)-4-methylcyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4′-({4-[trans-4-(2-hydroxyethoxy)-4-methylcyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.44 g), tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.29 mL),2,6-lutidine (0.15 mL) and tetrahydrofuran (5 mL) was stirred at 0° C.for 3 hr. The reaction mixture was diluted with ethyl acetate, washedwith water and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The residue obtained by silica gel column chromatography was dissolvedin dimethyl sulfoxide (5 mL), and the mixture was added to a mixture ofhydroxylammonium chloride (0.87 g), sodium hydrogen carbonate (1.4 g)and dimethyl sulfoxide (5 mL), which had been stirred in advance at 40°C. for 30 min. The reaction mixture was stirred at 90° C. for 16 hr,diluted with ethyl acetate, washed with water and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was dissolved intetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.16 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was dissolved in tetrahydrofuran (10 mL).Tetrabutylammonium bromide (1.0 M tetrahydrofuran solution, 2.1 mL) wasadded, and the mixture was stirred at room temperature for 3 hr. Thereaction mixture was extracted with 1 N hydrochloric acid and ethylacetate, and the ethyl acetate layer was washed with saturated brine andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.25 g, 51%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.4 Hz, 3H) 1.32 (s, 3H)1.46-1.66 (m, 6H) 1.74-1.85 (m, 2H) 2.57-2.74 (m, 2H) 2.88-2.98 (m, 2H)3.36-3.47 (m, 4H) 3.96 (s, 2H) 4.48 (t, J=5.1 Hz, 1H) 4.84-5.01 (m, 1H)7.19-7.25 (m, 2H) 7.27-7.33 (m, 2H) 7.53 (dd, J=16.8, 7.8 Hz, 2H)7.62-7.71 (m, 2H) 8.20 (s, 1H) 12.37 (s, 1H)

Example 1844-[trans-4-(1,3-oxazol-5-yl)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.6 g), sodium hydrogencarbonate (0.97 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-({4-[trans-4-(1,3-oxazol-5-yl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.3 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.11 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.95 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.098g, 29%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H), 1.45-1.62 (m, 4H),1.74-1.86 (m, 2H), 2.09-2.20 (m, 2H), 2.56-2.85 (m, 3H), 2.89-2.98 (m,2H), 3.97 (s, 2H), 4.91-5.04 (m, 1H), 6.91 (s, 1H), 7.20-7.26 (m, 2H),7.29-7.35 (m, 2H), 7.46-7.58 (m, 2H), 7.62-7.72 (m, 2H), 8.20 (s, 1H),8.23 (s, 1H), 12.38 (br. s., 1H)

Example 1854-[trans-4-(1,3-oxazol-5-yl)cyclohexyl]-7-propyl-6-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4′-({4-[trans-4-(1,3-oxazol-5-yl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.35 g), dibutyltin oxide (0.051 g), azidotrimethylsilane (2.3 g) andtoluene (15 mL) was stirred at 110° C. for 48 hr. The reaction mixturewas diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as colorlesscrystals (0.18 g, 46%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H), 1.45-1.62 (m, 4H),1.73-1.83 (m, 2H), 2.09-2.19 (m, 2H), 2.59-2.84 (m, 3H), 2.87-2.94 (m,2H), 3.92 (s, 2H), 4.89-5.03 (m, 1H), 6.91 (s, 1H), 6.99 (d, J=8.1 Hz,2H), 7.19 (d, J=8.1 Hz, 2H), 7.54 (dd, J=13.1, 7.1 Hz, 2H), 7.60-7.70(m, 2H), 8.20 (s, 1H), 8.23 (s, 1H)

Example 1864-[trans-4-(3-hydroxypropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4′-({4-[trans-4-(3-hydroxypropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.19 g), tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.097mL), 2,6-lutidine (0.049 mL) and tetrahydrofuran (5 mL) was stirred at0° C. for 3 hr. The reaction mixture was diluted with ethyl acetate,washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The residue obtained by silica gel column chromatography wasdissolved in dimethyl sulfoxide (5 mL), and the mixture was added to amixture of hydroxylammonium chloride (0.37 g), sodium hydrogen carbonate(0.59 g) and dimethyl sulfoxide (5 mL), which had been stirred inadvance at 40° C. for 30 min. The reaction mixture was stirred at 90° C.for 16 hr, diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was dissolved intetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.069 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.058 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was dissolved in tetrahydrofuran (10 mL).Tetrabutylammonium bromide (1.0 M tetrahydrofuran solution, 0.88 mL) wasadded, and the mixture was stirred at room temperature for 3 hr. Thereaction mixture was extracted with 1 N hydrochloric acid and ethylacetate, and the ethyl acetate layer was washed with saturated brine andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.1 g, 49%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H), 1.17-1.34 (m, 2H),1.45-1.75 (m, 6H), 2.03-2.14 (m, 2H), 2.52-2.64 (m, 2H), 2.87-2.99 (m,2H), 3.22-3.30 (m, 1H), 3.41-3.54 (m, 4H), 3.95 (s, 2H), 4.36 (t, J=5.2Hz, 1H), 4.90 (t, J=12.2 Hz, 1H), 7.19-7.24 (m, 2H), 7.27-7.34 (m, 2H),7.53 (dd, J=17.1, 7.7 Hz, 2H), 7.61-7.72 (m, 2H), 8.18 (s, 1H), 12.38(br. s., 1H)

Example 1876-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-(2-oxo-1,4-dioxaspiro[4.5]dec-8-yl)-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4-(4-oxocyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.2 g), trimethylsilyl [(trimethylsilyl)oxy]acetate (0.16 mL),tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.18 mL) andmethylene chloride (5 mL) was stirred at −78° C. for 1 hr, and then atroom temperature for 16 hr. The reaction mixture was diluted with ethylacetate, washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.066g, 26%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H), 1.46-1.61 (m, 2H),1.64-1.76 (m, 2H), 1.89-2.12 (m, 4H), 2.76-2.97 (m, 4H), 3.96 (s, 2H),4.52 (s, 2H), 4.95-5.15 (m, 1H), 7.18-7.25 (m, 2H), 7.27-7.37 (m, 2H),7.53 (dd, J=17.0, 7.5 Hz, 2H), 7.62-7.72 (m, 2H), 8.19 (s, 1H), 12.38(br. s., 1H)

Example 1884-[4-(methoxyimino)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4-(4-oxocyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.2 g), (aminooxy)methane hydrochloride (0.32 g) and pyridine (10 mL)was stirred at 100° C. for 16 hr. Ethyl acetate and water were added tothe reaction mixture, and the mixture was adjusted to pH 4 with 1 Nhydrochloric acid. The ethyl acetate layer was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography to give the title compound as colorlesscrystals (0.15 g, 71%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H), 1.46-1.62 (m, 2H),1.75-2.00 (m, 3H), 2.22-2.45 (m, 2H), 2.52-2.71 (m, 2H), 2.88-2.98 (m,2H), 3.14-3.24 (m, 1H), 3.75 (s, 3H), 3.97 (s, 2H), 5.14-5.27 (m, 1H),7.18-7.26 (m, 2H), 7.28-7.35 (m, 2H), 7.47-7.59 (m, 2H), 7.62-7.73 (m,2H), 8.18 (s, 1H), 12.38 (s, 1H)

Example 1894-[trans-4-(hydroxymethyl)-4-methylcyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4′-({4-[trans-4-(hydroxymethyl)-4-methylcyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.22 g), tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.31 mL),2,6-lutidine (0.15 mL) and tetrahydrofuran (10 mL) was stirred at 0° C.for 3 hr. The reaction mixture was diluted with ethyl acetate, washedwith water and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The residue obtained by silica gel column chromatography was dissolvedin dimethyl sulfoxide (5 mL), and the mixture was added to a mixture ofhydroxylammonium chloride (0.46 g), sodium hydrogen carbonate (0.74 g)and dimethyl sulfoxide (10 mL), which had been stirred in advance at 40°C. for 30 min. The reaction mixture was stirred at 90° C. for 16 hr,diluted with ethyl acetate, washed with water and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was dissolved intetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.086 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.073 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was dissolved in tetrahydrofuran (10 mL).Tetrabutylammonium bromide (1.0 M tetrahydrofuran solution, 1.3 mL) wasadded, and the mixture was stirred at room temperature for 3 hr. Thereaction mixture was extracted with 1 N hydrochloric acid and ethylacetate, and the ethyl acetate layer was washed with saturated brine andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.065 g, 26%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84-0.97 (m, 6H), 1.13-1.28 (m, 2H),1.36-1.61 (m, 4H), 1.64-1.74 (m, 2H), 2.56-2.74 (m, 2H), 2.88-2.97 (m,2H), 3.49 (d, J=4.9 Hz, 2H), 3.96 (s, 2H), 4.46 (t, J=5.3 Hz, 1H),4.80-4.97 (m, 1H), 7.19-7.26 (m, 2H), 7.27-7.35 (m, 2H), 7.53 (dd,J=17.2, 7.4 Hz, 2H), 7.62-7.73 (m, 2H), 8.20 (s, 1H), 12.37 (s, 1H)

Example 1904-[cis-4-hydroxy-4-(morpholin-4-ylmethyl)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.46 g), sodium hydrogencarbonate (0.74 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-({4-[cis-4-hydroxy-4-(morpholin-4-ylmethyl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.25 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.085 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.073 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was poured into water, and the mixture was adjusted to pH 7 with1 N hydrochloric acid and extracted with ethyl acetate. The obtainedethyl acetate layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.12 g,44%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.4 Hz, 3H), 1.36-1.74 (m, 8H),2.25 (s, 2H), 2.50-2.55 (m, 4H), 2.81-2.99 (m, 4H), 3.53-3.64 (m, 4H),3.96 (s, 2H), 4.77-4.90 (m, 1H), 7.19-7.25 (m, 2H), 7.26-7.34 (m, 2H),7.52 (dd, J=16.7, 7.6 Hz, 2H), 7.61-7.72 (m, 2H), 8.18 (s, 1H), 12.25(br. s., 1H)

Example 1914-[4-(2-hydroxyethylidene)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4′-({4-[4-(2-hydroxyethylidene)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.25 g), tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.17 mL),2,6-lutidine (0.088 mL) and tetrahydrofuran (5 mL) was stirred at 0° C.for 3 hr. The reaction mixture was diluted with ethyl acetate, washedwith water and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The residue obtained by silica gel column chromatography was dissolvedin dimethyl sulfoxide (5 mL), and the mixture was added to a mixture ofhydroxylammonium chloride (0.53 g), sodium hydrogen carbonate (0.85 g)and dimethyl sulfoxide (10 mL), which had been stirred in advance at 40°C. for 30 min. The reaction mixture was stirred at 90° C. for 16 hr,diluted with ethyl acetate, washed with water and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was dissolved intetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.098 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.083 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was dissolved in tetrahydrofuran (10 mL).Tetrabutylammonium bromide (1.0 M tetrahydrofuran solution, 1.3 mL) wasadded, and the mixture was stirred at room temperature for 3 hr. Thereaction mixture was extracted with 1 N hydrochloric acid and ethylacetate, and the ethyl acetate layer was washed with saturated brine andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.04 g,14%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H), 1.47-1.60 (m, 2H),1.70-1.92 (m, 3H), 2.09-2.32 (m, 2H), 2.42-2.75 (m, 3H), 2.87-2.98 (m,2H), 3.88-4.04 (m, 4H), 4.53 (t, J=5.3 Hz, 1H), 5.01-5.18 (m, 1H), 5.32(t, J=6.7 Hz, 1H), 7.18-7.25 (m, 2H), 7.28-7.35 (m, 2H), 7.47-7.58 (m,2H), 7.61-7.72 (m, 2H), 8.13-8.18 (m, 1H), 12.38 (br. s., 1H)

Example 1924-[4-hydroxy-4-(trifluoromethyl)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.54 g), sodium hydrogencarbonate (0.88 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-({4-[4-hydroxy-4-(trifluoromethyl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.28 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.1 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.086 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.16 g,51%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.3 Hz, 3H), 1.50-1.74 (m, 6H),1.81-1.93 (m, 2H), 2.84-3.02 (m, 4H), 3.99 (s, 2H), 4.87-5.00 (m, 1H),5.88 (s, 1H), 7.19-7.27 (m, 2H), 7.29-7.35 (m, 2H), 7.47-7.60 (m, 2H),7.61-7.74 (m, 2H), 8.20 (s, 1H), 12.39 (br. s., 1H)

Example 1934-{4-[(1-methylethoxy)imino]cyclohexyl}-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4-(4-oxocyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.2 g), 2-(aminooxy)propane hydrochloride (0.43 g) and pyridine (10 mL)was stirred at 100° C. for 16 hr. Ethyl acetate and water were added tothe reaction mixture, and the mixture was adjusted to pH 4 with 1 Nhydrochloric acid. The ethyl acetate layer was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography to give the title compound as colorlesscrystals (0.18 g, 79%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H), 1.18 (t, J=6.1 Hz,6H), 1.46-1.62 (m, 2H), 1.76-1.99 (m, 3H), 2.22-2.46 (m, 2H), 2.52-2.74(m, 2H), 2.88-2.98 (m, 2H), 3.17-3.26 (m, 1H), 3.97 (s, 2H), 4.15-4.28(m, 1H), 5.13-5.27 (m, 1H), 7.18-7.26 (m, 2H), 7.28-7.35 (m, 2H),7.46-7.59 (m, 2H), 7.62-7.72 (m, 2H), 8.18 (s, 1H), 12.38 (br. s., 1H)

Example 1944-[trans-4-(2-hydroxy-2-methylpropoxy)-4-methylcyclohexyl]-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.2 g), sodium hydrogencarbonate (0.33 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-({4-[trans-4-(2-hydroxypropoxy)-4-methylcyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.11 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.038 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.032 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.047 g, 37%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H), 1.07 (s, 6H), 1.31(s, 3H), 1.44-1.67 (m, 6H), 1.73-1.83 (m, 2H), 2.36 (s, 3H), 2.57-2.76(m, 2H), 2.83-2.94 (m, 2H), 3.12 (s, 2H), 3.93 (s, 2H), 4.15 (s, 1H),4.81-4.95 (m, 1H), 7.19-7.24 (m, 2H), 7.26-7.32 (m, 2H), 7.47-7.57 (m,2H), 7.61-7.71 (m, 2H), 12.37 (br. s., 1H)

Example 1956-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl-4-{4-[(tetrahydro-2H-pyran-4-yloxy)imino]cyclohexyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4-(4-oxocyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.2 g), 4-(aminooxy)tetrahydro-2H-pyran (0.45 g) and pyridine (5 mL)was stirred at 100° C. for 16 hr. Ethyl acetate and water were added tothe reaction mixture, and the mixture was adjusted to pH 4 with 1 Nhydrochloric acid. The ethyl acetate layer was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography to give the title compound as colorlesscrystals (0.18 g, 76%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H), 1.44-1.60 (m, 4H),1.75-2.04 (m, 5H), 2.23-2.47 (m, 2H), 2.53-2.70 (m, 2H), 2.87-2.99 (m,2H), 3.21-3.29 (m, 1H), 3.35-3.46 (m, 2H), 3.75-3.84 (m, 2H), 3.97 (s,2H), 4.09-4.25 (m, 1H), 5.12-5.28 (m, 1H), 7.17-7.26 (m, 2H), 7.28-7.36(m, 2H), 7.53 (dd, J=17.3, 7.5 Hz, 2H), 7.62-7.72 (m, 2H), 8.18 (s, 1H),12.38 (br. s., 1H)

Example 1964-{4-[(2-hydroxy-2-methylpropoxy)imino]cyclohexyl}-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4-(4-oxocyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.2 g), 1-(aminooxy)-2-methylpropan-2-ol (0.4 g) and pyridine (5 mL)was stirred at 100° C. for 16 hr. Ethyl acetate and water were added tothe reaction mixture, and the mixture was adjusted to pH 4 with 1 Nhydrochloric acid. The ethyl acetate layer was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography to give the title compound as colorlesscrystals (0.15 g, 63%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H), 1.11 (s, 6H),1.47-1.62 (m, 2H), 1.79-2.02 (m, 3H), 2.21-2.45 (m, 2H), 2.53-2.71 (m,2H), 2.89-2.97 (m, 2H), 3.26-3.36 (m, 1H), 3.79 (s, 2H), 3.97 (s, 2H),4.43 (s, 1H), 5.21 (t, J=11.8 Hz, 1H), 7.19-7.26 (m, 2H), 7.29-7.36 (m,2H), 7.53 (dd, J=17.1, 7.5 Hz, 2H), 7.62-7.73 (m, 2H), 8.18 (s, 1H),12.38 (br. s., 1H)

Example 1974-[trans-4-(2-ethyl-2-hydroxybutoxy)cyclohexyl]-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.27 g), sodium hydrogencarbonate (0.43 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-({4-[trans-4-(2-ethyl-2-hydroxybutoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.15 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.05 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.043 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.08 g, 48%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.80 (t, J=7.4 Hz, 6H), 0.92 (t, J=7.2 Hz,3H), 1.15-1.42 (m, 6H), 1.45-1.58 (m, 2H), 1.62-1.72 (m, 2H), 2.05-2.15(m, 2H), 2.35 (s, 3H), 2.51-2.63 (m, 2H), 2.84-2.92 (m, 2H), 3.22 (s,2H), 3.25-3.29 (m, 1H), 3.93 (s, 2H), 4.78-4.93 (m, 1H), 7.17-7.31 (m,4H), 7.52 (dd, J=16.7, 7.6 Hz, 2H), 7.61-7.72 (m, 2H), 12.37 (br. s.,1H)

Example 1984-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-2-methyl-7-propyl-6-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.32 g), dibutyltin oxide (0.072 g), azidotrimethylsilane (2 g) andtoluene (15 mL) was stirred at 110° C. for 48 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumfluoride solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The residue obtained by purification by silica gel columnchromatography was dissolved in tetrahydrofuran (5 mL).Tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 0.67 mL) wasadded and the mixture was stirred at 70° C. for 1 hr. The reactionmixture was extracted with ethyl acetate and 1 N hydrochloric acid, andthe ethyl acetate layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.16 g,45%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (t, J=7.3 Hz, 3H) 1.05-1.10 (m, 6H)1.18-1.35 (m, 2H) 1.43-1.58 (m, 2H) 1.62-1.73 (m, 2H) 2.05-2.15 (m, 2H)2.35 (s, 3H) 2.53-2.64 (m, 2H) 2.79-2.91 (m, 2H) 3.20 (s, 2H) 3.87 (s,2H) 4.23 (s, 1H) 4.78-4.94 (m, 1H) 6.98 (d, J=8.1 Hz, 2H) 7.16 (d, J=8.1Hz, 2H) 7.48-7.58 (m, 2H) 7.60-7.70 (m, 2H)

Example 1994-[trans-4-(2-ethyl-2-hydroxybutoxy)cyclohexyl]-2-methyl-7-propyl-6-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.25 g), dibutyltin oxide (0.054 g), azidotrimethylsilane (1.5 g) andtoluene (15 mL) was stirred at 110° C. for 48 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumfluoride solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The residue obtained by purification by silica gel columnchromatography was dissolved in tetrahydrofuran (5 mL).Tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 0.4 mL) wasadded and the mixture was stirred at 70° C. for 1 hr. Ethyl acetate and1 N hydrochloric acid were added to the reaction mixture, and themixture was extracted with ethyl acetate. The ethyl acetate layer waswashed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The obtained residuewas purified by silica gel column chromatography to give the titlecompound as colorless crystals (0.087 g, 32%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.80 (t, J=7.4 Hz, 6H), 0.90 (t, J=7.3 Hz,3H), 1.21-1.31 (m, 2H), 1.38 (d, J=7.5 Hz, 4H), 1.44-1.56 (m, 2H),1.62-1.72 (m, 2H), 2.04-2.16 (m, 2H), 2.35 (s, 3H), 2.52-2.63 (m, 2H),2.81-2.90 (m, 2H), 3.22 (s, 2H), 3.84-3.92 (m, 3H), 4.76-4.93 (m, 1H),6.98 (d, J=8.1 Hz, 2H), 7.16 (d, J=8.1 Hz, 2H), 7.48-7.58 (m, 2H),7.59-7.71 (m, 2H)

Example 2004-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-2-methyl-7-propyl-6-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

4-[trans-4-(2-Hydroxy-2-methylpropoxy)cyclohexyl]-2-methyl-7-propyl-6-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.09 g) was suspended in isopropyl alcohol (3 mL), 0.5N potassiumhydroxide solution (0.3 mL) was added, and the solvent was evaporatedunder reduced pressure. The residue was solidified with diisopropylether to give the title compound as a colorless solid (0.086 g, 90%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.3 Hz, 3H), 1.07 (s, 6H),1.20-1.36 (m, 2H), 1.50-1.72 (m, 4H), 2.03-2.14 (m, 2H), 2.34 (s, 3H),2.53-2.63 (m, 2H), 2.82-2.91 (m, 2H), 3.20 (s, 2H), 3.83 (s, 2H), 4.24(s, 1H), 4.86 (t, J=12.7 Hz, 1H), 6.97-7.08 (m, 4H), 7.24-7.38 (m, 3H),7.46-7.54 (m, 1H)

Example 2014-[trans-4-(2-ethyl-2-hydroxybutoxy)cyclohexyl]-2-methyl-7-propyl-6-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

4-[trans-4-(2-Ethyl-2-hydroxybutoxy)cyclohexyl]-2-methyl-7-propyl-6-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.063 g) was suspended in isopropyl alcohol (3 mL), 0.5N potassiumhydroxide solution (0.2 mL) was added, and the solvent was evaporatedunder reduced pressure. The residue was solidified with diisopropylether to give the title compound as a colorless solid (0.045 g, 67%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.80 (t, J=7.4 Hz, 6H) 0.94 (t, J=7.3 Hz,3H) 1.17-1.42 (m, 6H) 1.50-1.73 (m, 4H) 2.03-2.16 (m, 2H) 2.34 (s, 3H)2.52-2.64 (m, 2H) 2.83-2.91 (m, 2H) 3.22 (s, 2H) 3.83 (s, 2H) 3.91 (s,1H) 4.79-4.92 (m, 1H) 6.97-7.07 (m, 4H) 7.24-7.39 (m, 3H) 7.46-7.52 (m,1H)

Example 2024-[trans-4-(2-ethyl-2-hydroxybutoxy)cyclohexyl]-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

4-[trans-4-(2-Ethyl-2-hydroxybutoxy)cyclohexyl]-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.082 g) was suspended in isopropyl alcohol (3 mL), 0.5N potassiumhydroxide solution (0.26 mL) was added, and the solvent was evaporatedunder reduced pressure. The residue was solidified with diisopropylether to give the title compound as a colorless solid (0.046 g, 53%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.80 (t, J=7.4 Hz, 6H) 0.95 (t, J=7.3 Hz,3H) 1.37 (q, J=7.4 Hz, 6H) 1.52-1.74 (m, 4H) 2.03-2.15 (m, 2H) 2.35 (s,3H) 2.52-2.65 (m, 2H) 2.83-2.93 (m, 2H) 3.22 (s, 2H) 3.84-3.94 (m, 3H)4.86 (t, J=11.8 Hz, 1H) 7.12-7.23 (m, 4H) 7.25-7.49 (m, 4H)

Example 2034-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-7-propyl-6-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.2 g), dibutyltin oxide (0.046 g), azidotrimethylsilane (1.3 g) andtoluene (15 mL) was stirred at 110° C. for 48 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumfluoride solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The obtained residue was dissolved in tetrahydrofuran (10 mL).Tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 0.93 mL) wasadded and the mixture was stirred at 70° C. for 1 hr. Ethyl acetate and1 N hydrochloric acid were added to the reaction mixture, and themixture was extracted with ethyl acetate. The ethyl acetate layer waswashed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The obtained residuewas purified by silica gel column chromatography to give the titlecompound as colorless crystals (0.033 g, 15%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91 (t, J=7.4 Hz, 3H), 1.08 (s, 6H),1.21-1.36 (m, 2H), 1.44-1.59 (m, 2H), 1.63-1.75 (m, 2H), 2.05-2.16 (m,2H), 2.51-2.67 (m, 2H), 2.84-2.95 (m, 2H), 3.20 (s, 2H), 3.85 (s, 2H),4.24 (s, 1H), 4.90 (t, J=12.1 Hz, 1H), 6.99 (d, J=8.0 Hz, 2H), 7.18 (d,J=8.0 Hz, 2H), 7.54 (dd, J=13.4, 7.4 Hz, 2H), 7.60-7.71 (m, 2H), 8.18(s, 1H)

Example 2044-[(5R,8R)-3-methyl-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.46 g), sodium hydrogencarbonate (0.74 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-({4-[(5R,8R)-3-methyl-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.23 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.086 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.073 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.12 g,47%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.4 Hz, 3H), 1.46-1.84 (m, 8H),1.92 (s, 3H), 2.54-2.72 (m, 2H), 2.87-2.98 (m, 4H), 3.98 (s, 2H), 4.97(t, J=12.3 Hz, 1H), 7.18-7.26 (m, 2H), 7.28-7.35 (m, 2H), 7.47-7.58 (m,2H), 7.62-7.73 (m, 2H), 8.20 (s, 1H), 12.39 (br. s., 1H)

Example 2054-[(5S,8S)-3-methyl-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.4 g), sodium hydrogencarbonate (0.65 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-({4-[(5S,8S)-3-methyl-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.2 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.075 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.063 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.078 g, 35%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.4 Hz, 3H), 1.47-1.73 (m, 6H),1.82-1.92 (m, 5H), 2.71 (s, 2H), 2.75-2.99 (m, 4H), 3.96 (s, 2H),4.89-5.04 (m, 1H), 7.18-7.25 (m, 2H), 7.28-7.35 (m, 2H), 7.46-7.58 (m,2H), 7.62-7.70 (m, 2H), 8.20 (s, 1H), 12.38 (br. s., 1H)

Example 2067-butyl-4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.58 g), sodium hydrogencarbonate (0.93 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-({7-butyl-4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.32 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.11 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.092 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.2 g, 56%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (t, J=7.2 Hz, 3H), 1.00 (s, 3H), 1.03(d, J=6.4 Hz, 3H), 1.08 (s, 3H), 1.21-1.54 (m, 6H), 1.63-1.74 (m, 2H),1.96-2.15 (m, 2H), 2.58 (t, J=11.9 Hz, 2H), 2.89-2.97 (m, 2H), 3.25 (q,J=6.1 Hz, 1H), 3.34-3.43 (m, 1H), 3.95 (s, 2H), 4.06 (s, 1H), 4.90 (t,J=12.3 Hz, 1H), 7.19-7.25 (m, 2H), 7.27-7.32 (m, 2H), 7.46-7.58 (m, 2H),7.62-7.73 (m, 2H), 8.18 (s, 1H), 12.39 (s, 1H)

Example 2074-(trans-4-{[(3R,4S)-4-hydroxytetrahydrofuran-3-yl]oxy}cyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4′-({5-oxo-7-propyl-4-[(3a′R,6a′S)-tetrahydrospiro[cyclohexane-1,2′-furo[3,4-d][1,3]dioxol]-4-yl]-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.14 g), tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.087mL), 2,6-lutidine (0.044 mL) and tetrahydrofuran (5 mL) was stirred at0° C. for 3 hr. The reaction mixture was diluted with ethyl acetate,washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The residue obtained by silica gel column chromatography wasdissolved in dimethyl sulfoxide (5 mL), and the mixture was added to amixture of hydroxylammonium chloride (0.26 g), sodium hydrogen carbonate(0.42 g) and dimethyl sulfoxide (5 mL), which had been stirred inadvance at 40° C. for 30 min. The reaction mixture was stirred at 90° C.for 16 hr, diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was dissolved intetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.049 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.041 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was dissolved in tetrahydrofuran (10 mL).Tetrabutylammonium bromide (1.0 M tetrahydrofuran solution, 1.7 mL) wasadded, and the mixture was stirred at room temperature for 3 hr. Thereaction mixture was extracted with 1 N hydrochloric acid and ethylacetate, and the ethyl acetate layer was washed with saturated brine andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.04 g, 26%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.2 Hz, 3H), 1.22-1.41 (m, 2H),1.47-1.60 (m, 2H), 1.64-1.74 (m, 2H), 2.09-2.21 (m, 2H), 2.51-2.67 (m,2H), 2.89-2.97 (m, 2H), 3.44-3.56 (m, 3H), 3.74-3.84 (m, 2H), 3.96 (s,2H), 4.01-4.15 (m, 2H), 4.53 (d, J=5.3 Hz, 1H), 4.84-4.97 (m, 1H),7.19-7.25 (m, 2H), 7.27-7.34 (m, 2H), 7.53 (dd, J=16.7, 7.6 Hz, 2H),7.63-7.74 (m, 2H), 8.18 (s, 1H), 12.38 (s, 1H)

Example 2087-butyl-4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

7-Butyl-4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.17 g) was suspended in isopropyl alcohol (3 mL), 2N potassiumhydroxide solution (0.14 mL) was added, and the solvent was evaporatedunder reduced pressure. The residue was solidified with diisopropylether to give the title compound as a colorless solid (0.15 g, 85%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.85 (t, J=7.3 Hz, 3H), 1.00 (s, 3H), 1.04(d, J=6.0 Hz, 3H), 1.08 (s, 3H), 1.20-1.56 (m, 6H), 1.71 (s, 2H),1.95-2.13 (m, 2H), 2.52-2.66 (m, 2H), 2.91-3.01 (m, 2H), 3.21-3.28 (m,1H), 3.35-3.43 (m, 1H), 3.90 (s, 2H), 4.06 (s, 1H), 4.90 (t, J=12.0 Hz,1H), 7.13-7.49 (m, 8H), 8.16 (s, 1H)

Example 2092-({trans-4-[5-oxo-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl]cyclohexyl}oxy)acetamide

A mixture of ethyl[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate(0.68 g), 1N aqueous sodium hydroxide solution (10 mL), tetrahydrofuran(10 mL) and methanol (10 mL) was stirred at room temperature for 1 hr. 1N Hydrochloric acid was added to the reaction mixture, and the mixturewas extracted with ethyl acetate. The obtained ethyl acetate layer waswashed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The obtained residuewas dissolved in N,N-dimethylformamide (5 mL), 1-hydroxybenzotriazoleammonium salt (0.25 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.28 g) were added, and the mixture was stirred at roomtemperature for 3 hr. The reaction mixture was diluted with ethylacetate, washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The residue obtained by purification by silica gel columnchromatography was dissolved in dimethyl sulfoxide (5 mL), and themixture was added to a mixture of hydroxylammonium chloride (0.45 g),sodium hydrogen carbonate (0.77 g) and dimethyl sulfoxide (5 mL), whichhad been stirred in advance at 40° C. for 30 min. The reaction mixturewas stirred at 90° C. for 16 hr, diluted with ethyl acetate, washed withwater and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was dissolved in tetrahydrofuran (5 mL).N,N′-Carbonyldiimidazole (0.089 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.075 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.16 g,13%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H), 1.26-1.43 (m, 2H),1.47-1.61 (m, 2H), 1.68-1.78 (m, 2H), 2.09-2.20 (m, 2H), 2.52-2.68 (m,2H), 2.88-2.98 (m, 2H), 3.46-3.59 (m, 1H), 3.96 (s, 2H), 4.53 (s, 2H),4.93 (t, J=8.3 Hz, 1H), 7.18-7.26 (m, 2H), 7.28-7.35 (m, 2H), 7.47-7.59(m, 2H), 7.62-7.73 (m, 2H), 8.19 (s, 1H)

Example 210({trans-4-[5-oxo-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl]cyclohexyl}oxy)acetonitrile

To a solution (10 mL) of2-({trans-4-[5-oxo-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl]cyclohexyl}oxy)acetamide(0.16 g) and pyridine (0.089 mL) in tetrahydrofuran was addedtrifluoroacetic acid anhydride (0.12 mL) at 0° C., and the mixture wasstirred for 2 hr. The reaction mixture was diluted with ethyl acetate,washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.059 g, 38%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H), 1.26-1.43 (m, 2H),1.47-1.61 (m, 2H), 1.68-1.78 (m, 2H), 2.09-2.20 (m, 2H), 2.52-2.68 (m,2H), 2.88-2.98 (m, 2H), 3.46-3.59 (m, 1H), 3.96 (s, 2H), 4.53 (s, 2H),4.93 (t, J=8.3 Hz, 1H), 7.18-7.26 (m, 2H), 7.28-7.35 (m, 2H), 7.47-7.59(m, 2H), 7.62-7.73 (m, 2H), 8.19 (s, 1H)

Example 2114-[(5R,8R)-3-(1-hydroxy-1-methylethyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.23 g), sodium hydrogencarbonate (0.37 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-({4-[(5R,8R)-3-(1-hydroxy-1-methylethyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.12 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.042 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.036 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.046 g, 34%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.06 (t, J=7.35 Hz, 3H) 1.51 (s, 6H)1.65-1.99 (m, 8H) 2.66-2.84 (m, 2H) 2.97-3.08 (m, 4H) 4.02 (s, 2H)5.04-5.18 (m, 1H) 7.33-7.52 (m, 6H) 7.59-7.67 (m, 1H) 7.75 (dd, J=7.72,0.94 Hz, 1H) 7.93 (s, 1H)

Example 2124-[(5S,8S)-3-(1-hydroxy-1-methylethyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.18 g), sodium hydrogencarbonate (0.3 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-({4-[(5S,8S)-3-(1-hydroxy-1-methylethyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.1 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.034 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.029 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.038 g, 34%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H) 1.32 (s, 6H)1.47-1.75 (m, 6H) 1.83-1.96 (m, 2H) 2.77-2.98 (m, 6H) 3.98 (s, 2H)4.90-5.04 (m, 1H) 5.13 (s, 1H) 7.18-7.25 (m, 2H) 7.29-7.35 (m, 2H)7.46-7.59 (m, 2H) 7.61-7.73 (m, 2H) 8.20 (s, 1H) 12.38 (br. s., 1H)

Example 2134-{trans-4-[(3-methyl-4,5-dihydroisoxazol-5-yl)methoxy]cyclohexyl}-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.85 g), sodium hydrogencarbonate (1.4 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-[(4-{trans-4-[(3-methyl-4,5-dihydroisoxazol-5-yl)methoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.46 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.16 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.13 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.22 g, 43%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.2 Hz, 3H) 1.20-1.36 (m, 2H)1.46-1.75 (m, 4H) 1.89 (s, 3H) 2.04-2.16 (m, 2 H) 2.53-2.76 (m, 3H)2.88-3.05 (m, 3H) 3.33-3.42 (m, 1H) 3.44-3.50 (m, 2H) 3.95 (s, 2H)4.49-4.64 (m, 1H) 4.83-4.97 (m, 1H) 7.18-7.24 (m, 2H) 7.27-7.34 (m, 2H)7.45-7.58 (m, 2H) 7.63-7.72 (m, 2H) 8.18 (s, 1H) 12.38 (s, 1H)

Example 2144-{trans-4-[(3-methyl-4,5-dihydroisoxazol-5-yl)methoxy]cyclohexyl}-7-propyl-6-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4′-[(4-{trans-4-[(3-methyl-4,5-dihydroisoxazol-5-yl)methoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.4 g), dibutyltin oxide (0.088 g), azidotrimethylsilane (2.4 g) andtoluene (25 mL) was stirred at 110° C. for 48 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumfluoride solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.15 g, 35%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91 (t, J=7.4 Hz, 3H) 1.20-1.36 (m, 2H)1.44-1.58 (m, 2H) 1.63-1.72 (m, 2H) 1.89 (s, 3H) 2.03-2.15 (m, 2H)2.53-2.75 (m, 3H) 2.85-3.04 (m, 3H) 3.33-3.41 (m, 1H) 3.47 (d, J=5.7 Hz,2H) 3.90 (s, 2H) 4.50-4.61 (m, 1H) 4.81-4.97 (m, 1H) 6.98 (d, J=8.3 Hz,2H) 7.18 (d, J=8.3 Hz, 2H) 7.48-7.59 (m, 2H) 7.60-7.71 (m, 2H) 8.17 (s,1H)

Example 2156-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-oxopropoxy)cyclohexyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.73 g), sodium hydrogencarbonate (1.2 g) and dimethyl sulfoxide (10 mL) was stirred at 50° C.for 30 min,4′-({4-[trans-4-(2-{[tert-butyl(dimethyl)silyl]oxy}propoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.35 g) was added, and the mixture was stirred at 90° C. for 20 hr.After allowing to cool to room temperature, ethyl acetate and water wereadded to the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with water and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography, and dissolved in tetrahydrofuran (10mL). N,N′-Carbonyldiimidazole (0.14 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.12 mL) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 1 N hydrochloric acid and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). Tetrabutylammonium fluoride (1 Mtetrahydrofuran solution, 1.8 mL) was added, and the mixture was stirredat room temperature for 3 hr. The reaction mixture was extracted withethyl acetate and water, and the organic layer was washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue obtainedby purification by silica gel column chromatography was dissolved inacetonitrile (15 mL), Dess-Martin reagent (0.42 g) was added, and themixture was stirred at room temperature for 2 hr. Saturated aqueoussodium hydrogen carbonate solution and sodium thiosulfate were added tothe reaction mixture, and the mixture was stirred at room temperaturefor 2 hr, and extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography to give the title compoundas colorless crystals (0.13 g, 31%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H) 1.22-1.40 (m, 2H)1.46-1.76 (m, 4H) 2.05 (s, 3H) 2.08-2.18 (m, 2H) 2.52-2.66 (m, 2H)2.88-2.97 (m, 2H) 3.33-3.41 (m, 1H) 3.96 (s, 2H) 4.16 (s, 2H) 4.85-4.99(m, 1H) 7.19-7.25 (m, 2H) 7.28-7.34 (m, 2H) 7.47-7.58 (m, 2H) 7.61-7.74(m, 2H) 8.18 (s, 1H) 12.38 (br. s., 1H)

Example 2164-(trans-4-{[(2E)-2-(methoxyimino)propyl]oxy}cyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-oxopropoxy)cyclohexyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.095 g), (aminooxy)methane hydrochloride (0.041 g) and pyridine (5 mL)was stirred at 80° C. for 16 hr. Ethyl acetate and water were added tothe reaction mixture, and the mixture was adjusted to pH 4 with 1 Nhydrochloric acid. The ethyl acetate layer was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography to give the title compound as colorlesscrystals (0.07 g, 70%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H) 1.22-1.76 (m, 6H)1.80 (s, 3H) 2.05-2.15 (m, 2H) 2.52-2.64 (m, 2H) 2.89-2.97 (m, 2H)3.27-3.35 (m, 1H) 3.78 (s, 3H) 3.93-3.99 (m, 4H) 4.85-4.98 (m, 1H)7.19-7.24 (m, 2H) 7.28-7.34 (m, 2H) 7.46-7.58 (m, 2H) 7.62-7.72 (m, 2H)8.18 (s, 1H) 12.38 (s, 1H)

Example 2174-(trans-4-{[(1R,2S)-2-hydroxycyclopentyl]oxy}cyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.6 g), sodium hydrogencarbonate (2.5 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[4-(trans-4-{[(1R,2S)-2-hydroxycyclopentyl]oxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.82 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.16 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.22 g,24%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H) 1.22-1.77 (m, 12H)2.04-2.21 (m, 2H) 2.52-2.65 (m, 2H) 2.87-2.98 (m, 2H) 3.38-3.51 (m, 1H)3.70-3.78 (m, 1H) 3.87-3.99 (m, 4H) 4.84-4.97 (m, 1H) 7.18-7.24 (m, 2H)7.28-7.34 (m, 2H) 7.47-7.59 (m, 2H) 7.62-7.74 (m, 2H) 8.18 (s, 1H) 12.38(s, 1H)

Example 2184-{trans-4-[(2-oxocyclopentyl)oxy]cyclohexyl}-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4-(trans-4-{[(1R,2S)-2-hydroxycyclopentyl]oxy}cyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.15 g), Dess-Martin reagent (0.2 g) and acetonitrile (10 mL) wasstirred at room temperature for 2 hr. Saturated aqueous sodium hydrogencarbonate solution and sodium thiosulfate were added to the reactionmixture, and the mixture was stirred at room temperature for 2 hr, andextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography to give the title compound ascolorless crystals (0.09 g, 62%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H) 1.20-1.40 (m, 2H)1.46-1.76 (m, 6H) 1.80-1.95 (m, 1H) 2.03-2.30 (m, 5H) 2.52-2.66 (m, 2H)2.88-2.98 (m, 2H) 3.51-3.64 (m, 1H) 3.92-4.08 (m, 3H) 4.91 (t, J=11.9Hz, 1H) 7.19-7.25 (m, 2H) 7.27-7.34 (m, 2H) 7.47-7.58 (m, 2H) 7.63-7.72(m, 2H) 8.18 (s, 1H) 12.38 (s, 1H)

Example 219({trans-4-[5-oxo-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl]cyclohexyl}oxy)acetonitrilepotassium salt

({trans-4-[5-Oxo-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl]cyclohexyl}oxy)acetonitrile(0.023 g) was suspended in isopropyl alcohol (5 mL), 0.5N potassiumhydroxide solution (0.082 mL) was added, and the solvent was evaporatedunder reduced pressure. The residue was solidified with diisopropylether to give the title compound as a colorless solid (0.014 g, 57%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.96 (t, J=7.3 Hz, 3H) 1.27-1.43 (m, 2H)1.52-1.80 (m, 4H) 2.09-2.20 (m, 2H) 2.52-2.67 (m, 2H) 2.90-3.00 (m, 2H)3.45-3.58 (m, 1H) 3.91 (s, 2H) 4.51 (s, 2H) 4.86-4.99 (m, 1H) 7.14-7.49(m, 8H) 8.17 (s, 1H)

Example 2204-{trans-4-[(1-hydroxycyclopropyl)methoxy]cyclohexyl}-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.41 g), sodium hydrogencarbonate (0.66 g) and dimethyl sulfoxide (10 mL) was stirred at 50° C.for 30 min,4′-[(4-{trans-4-[(1-{[tert-butyl(dimethyl)silyl]oxy}cyclopropyl)methoxy]cyclohexyl}-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.26 g) was added, and the mixture was stirred at 90° C. for 20 hr.After allowing to cool to room temperature, ethyl acetate and water wereadded to the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with water and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography, and dissolved in tetrahydrofuran (5mL). N,N′-Carbonyldiimidazole (0.076 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.064 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with 1 N hydrochloric acid andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). Tetrabutylammonium fluoride (1 Mtetrahydrofuran solution, 0.98 mL) was added, and the mixture wasstirred at room temperature for 3 hr. The reaction mixture was extractedwith ethyl acetate and water, and the organic layer was washed withwater and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was solidified with diisopropyl ether to give the title compoundas a colorless solid (0.084 g, 35%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.42-0.49 (m, 2H) 0.51-0.57 (m, 2H) 0.92 (t,J=7.3 Hz, 3H) 1.19-1.74 (m, 6H) 2.06-2.17 (m, 2H) 2.35 (s, 3H) 2.52-2.65(m, 2H) 2.84-2.92 (m, 2H) 3.35-3.42 (m, 1H) 3.44 (s, 2H) 3.93 (s, 2H)4.79-4.93 (m, 1H) 5.28 (s, 1H) 7.19-7.24 (m, 2H) 7.26-7.31 (m, 2H) 7.52(dd, J=16.6, 7.5 Hz, 2H) 7.61-7.71 (m, 2H) 12.39 (br. s., 1H)

Example 2214-[trans-4-(2-hydroxypropoxy)cyclohexyl]-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.42 g), sodium hydrogencarbonate (0.68 g) and dimethyl sulfoxide (10 mL) was stirred at 50° C.for 30 min,4′-({4-[trans-4-(2-{[tert-butyl(dimethyl)silyl]oxy}propoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.27 g) was added, and the mixture was stirred at 90° C. for 20 hr.After allowing to cool to room temperature, ethyl acetate and water wereadded to the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with water and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography, and dissolved in tetrahydrofuran (10mL). N,N′-Carbonyldiimidazole (0.079 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.067 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with 1 N hydrochloric acid andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). Tetrabutylammonium fluoride (1 Mtetrahydrofuran solution, 1 mL) was added, and the mixture was stirredat room temperature for 3 hr. Ethyl acetate and water were added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was solidified with diisopropyl etherto give the title compound as a colorless solid (0.13 g, 54%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H) 1.03 (d, J=6.4 Hz,3H) 1.18-1.34 (m, 2H), 1.46-1.73 (m, 4H) 2.04-2.15 (m, 2H) 2.35 (s, 3H)2.51-2.64 (m, 2H) 2.83-2.92 (m, 2H) 3.19-3.37 (m, 3H) 3.62-3.75 (m, 1H)3.93 (s, 2H) 4.50 (d, J=4.7 Hz, 1H) 4.79-4.93 (m, 1H) 7.18-7.24 (m, 2H)7.26-7.32 (m, 2H) 7.47-7.58 (m, 2H) 7.62-7.72 (m, 2H) 12.36 (s, 1H)

Example 2224-[trans-4-(2-hydroxybutoxy)cyclohexyl]-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.46 g), sodium hydrogencarbonate (0.74 g) and dimethyl sulfoxide (10 mL) was stirred at 50° C.for 30 min,4′-({4-[trans-4-(2-{[tert-butyl(dimethyl)silyl]oxy}butoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.29 g) was added, and the mixture was stirred at 90° C. for 20 hr.After allowing to cool to room temperature, ethyl acetate and water wereadded to the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with water and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography, and dissolved in tetrahydrofuran (10mL). N,N′-Carbonyldiimidazole (0.086) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.073 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with 1 N hydrochloric acid andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). Tetrabutylammonium fluoride (1 Mtetrahydrofuran solution, 1.1 mL) was added, and the mixture was stirredat room temperature for 3 hr. Ethyl acetate and water were added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was solidified with diisopropyl etherto give the title compound as a colorless solid (0.12 g, 45%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.81-0.97 (m, 8H) 1.17-1.58 (m, 6H)1.63-1.73 (m, 2H) 2.05-2.15 (m, 2H) 2.35 (s, 3H) 2.51-2.66 (m, 2H)2.83-2.93 (m, 2H) 3.25-3.48 (m, 2H) 3.93 (s, 2H) 4.44 (d, J=5.1 Hz, 1H)4.86 (t, J=12.3 Hz, 1H) 7.18-7.24 (m, 2H) 7.26-7.31 (m, 2H) 7.46-7.58(m, 2H) 7.61-7.71 (m, 2H) 12.36 (s, 1H)

Example 2234-[trans-4-(2-hydroxypropoxy)cyclohexyl]-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

4-[trans-4-(2-Hydroxypropoxy)cyclohexyl]-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.11 g) was suspended in isopropyl alcohol (5 mL), 1N potassiumhydroxide solution (0.18 mL) was added, and the solvent was evaporatedunder reduced pressure. The residue was solidified with diisopropylether to give the title compound as a colorless solid (0.097 g, 87%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.3 Hz, 3H) 1.03-1.05 (m, 3H)1.18-1.37 (m, 2H) 1.50-1.75 (m, 4H) 2.04-2.17 (m, 2H) 2.35 (s, 3H)2.52-2.63 (m, 2H) 2.84-2.95 (m, 2H), 3.19-3.36 (m, 3H) 3.63-3.82 (m, 1H)3.88 (s, 2H) 4.28-4.56 (m, 1H) 4.80-4.92 (m, 1H) 7.11-7.50 (m, 7H)

Example 2244-[trans-4-(2-hydroxybutoxy)cyclohexyl]-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

4-[trans-4-(2-Hydroxybutoxy)cyclohexyl]-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.094 g) was suspended in isopropyl alcohol (5 mL), 1N potassiumhydroxide solution (0.15 mL) was added, and the solvent was evaporatedunder reduced pressure. The residue was solidified with diisopropylether to give the title compound as a colorless solid (0.089 g, 89%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.87 (t, J=7.3 Hz, 3H) 0.95 (t, J=7.3 Hz,3H) 1.16-1.74 (m, 8H) 2.04-2.16 (m, 2H) 2.35 (s, 3H) 2.51-2.64 (m, 2H)2.85-2.94 (m, 2H) 3.24-3.37 (m, 1H) 3.38-3.48 (m, 1H) 3.88 (s, 2H)4.31-4.49 (m, 1H) 4.78-4.94 (m, 1H) 7.12-7.49 (m, 8H)

Example 2254-[trans-4-(2-ethyl-2-hydroxybutoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.46 g), sodium hydrogencarbonate (0.74 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-({4-[trans-4-(2-ethyl-2-hydroxybutoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.25 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.086 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.073 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.18 g, 65%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.80 (t, J=7.5 Hz, 6H) 0.92 (t, J=7.5 Hz,3H) 1.17-1.31 (m, 2H) 1.38 (q, J=7.5 Hz, 4H) 1.46-1.74 (m, 4H) 2.05-2.15(m, 2H) 2.52-2.65 (m, 2H) 2.89-2.98 (m, 2H) 3.20-3.31 (m, 3H) 3.90 (s,1H) 3.96 (s, 2H) 4.91 (t, J=11.3 Hz, 1H) 7.19-7.25 (m, 2H) 7.27-7.35 (m,2H) 7.47-7.58 (m, 2H) 7.62-7.72 (m, 2H) 8.18 (s, 1H) 12.38 (s, 1H)

Example 2261-[({trans-4-[5-oxo-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl]cyclohexyl}oxy)methyl]cyclobutanecarboxamide

A mixture of hydroxylammonium chloride (0.66 g), sodium hydrogencarbonate (1.1 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,1-{[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]methyl}cyclobutanecarboxamide(0.37 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.12 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.26 g, 64%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H) 1.21-1.90 (m, 10H)2.06-2.27 (m, 4H) 2.51-2.67 (m, 2H) 2.88-2.97 (m, 2H) 3.27-3.38 (m, 1H)3.64 (s, 2H) 3.96 (s, 2H) 4.91 (t, J=12.1 Hz, 1H) 6.80 (s, 1H) 6.93 (s,1H) 7.19-7.24 (m, 2H) 7.28-7.33 (m, 2H) 7.47-7.58 (m, 2H) 7.62-7.72 (m,2H) 8.18 (s, 1H) 12.38 (s, 1H)

Example 2271-[({trans-4-[5-oxo-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl]cyclohexyl}oxy)methyl]cyclobutanecarbonitrile

To a solution (10 mL) of1-[({trans-4-[5-oxo-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl]cyclohexyl}oxy)methyl]cyclobutanecarboxamide(0.22 g) and pyridine (0.11 mL) in tetrahydrofuran was addedtrifluoroacetic acid anhydride (0.093 mL) at 0° C., and the mixture wasstirred for 30 min. The reaction mixture was diluted with ethyl acetate,washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.15 g, 69%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H) 1.26-1.42 (m, 2H)1.46-1.77 (m, 4H) 1.97-2.19 (m, 6H) 2.30-2.44 (m, 2H) 2.52-2.68 (m, 2H)2.89-2.97 (m, 2H) 3.37-3.50 (m, 1H) 3.69 (s, 2H) 3.96 (s, 2H) 4.93 (t,J=12.2 Hz, 1H) 7.20-7.24 (m, 2H) 7.28-7.34 (m, 2H) 7.47-7.58 (m, 2H)7.62-7.71 (m, 2H) 8.18 (s, 1H) 12.38 (br. s., 1H)

Example 2284-(trans-4-{[1-(hydroxymethyl)cyclobutyl]methoxy}cyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.48 g), sodium hydrogencarbonate (0.77 g) and dimethyl sulfoxide (10 mL) was stirred at 50° C.for 30 min,4′-{[4-(trans-4-{[1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclobutyl]methoxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.31 g) was added, and the mixture was stirred at 90° C. for 20 hr.After allowing to cool to room temperature, ethyl acetate and water wereadded to the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with water and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography, and dissolved in tetrahydrofuran (5mL). N,N′-Carbonyldiimidazole (0.089 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.075 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with 1 N hydrochloric acid andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (5 mL). Tetrabutylammonium fluoride (1 Mtetrahydrofuran solution, 1.1 mL) was added and the mixture was stirredat 70° C. for 3 hr. Ethyl acetate and water were added to the reactionmixture, and the mixture was extracted with ethyl acetate. The organiclayer was washed with water and then with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.22 g, 76%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H) 1.21-1.37 (m, 2H)1.46-1.84 (m, 10H) 2.05-2.17 (m, 2H) 2.52-2.66 (m, 2H) 2.88-2.97 (m, 2H)3.24-3.36 (m, 3H) 3.39 (s, 2H) 3.96 (s, 2H) 4.45 (t, J=5.3 Hz, 1H)4.84-4.97 (m, 1H) 7.18-7.25 (m, 2H) 7.28-7.34 (m, 2H) 7.46-7.58 (m, 2H)7.62-7.73 (m, 2H) 8.18 (s, 1H) 12.38 (br. s., 1H)

Example 2294-[trans-4-(2-ethyl-2-hydroxybutoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

4-[trans-4-(2-Ethyl-2-hydroxybutoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.15 g) was suspended in isopropyl alcohol (5 mL), 1N potassiumhydroxide solution (0.24 mL) was added, and the solvent was evaporatedunder reduced pressure. The residue was solidified with diisopropylether to give the title compound as a colorless solid (0.12 g, 74%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.80 (t, J=7.5 Hz, 6H) 0.96 (t, J=7.6 Hz,3H) 1.18-1.44 (m, 6H) 1.52-1.76 (m, 4H) 2.03-2.16 (m, 2H) 2.52-2.65 (m,2H) 2.89-3.00 (m, 2H) 3.19-3.31 (m, 3H) 3.91 (s, 3H) 4.91 (t, J=12.3 Hz,1H) 7.13-7.49 (m, 8H) 8.17 (s, 1H)

Example 2301-[({trans-4-[5-oxo-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl]cyclohexyl}oxy)methyl]cyclobutanecarbonitrilepotassium salt

1-[({trans-4-[5-Oxo-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl]cyclohexyl}oxy)methyl]cyclobutanecarbonitrile(0.12 g) was suspended in isopropyl alcohol (5 mL), 1N potassiumhydroxide solution (0.19 mL) was added, and the solvent was evaporatedunder reduced pressure. The residue was solidified with diisopropylether to give the title compound as a colorless solid (0.12 g, 74%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.96 (t, J=7.4 Hz, 3H) 1.26-1.42 (m, 2H)1.52-1.78 (m, 4H) 1.96-2.19 (m, 6H) 2.31-2.44 (m, 2H) 2.52-2.68 (m, 2H)2.91-3.00 (m, 2H) 3.37-3.49 (m, 1H) 3.69 (s, 2H) 3.91 (s, 2H) 4.92 (t,J=12.3 Hz, 1H) 7.14-7.50 (m, 8H) 8.16 (s, 1H)

Example 2316-{[2-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.47 g), sodium hydrogencarbonate (0.75 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,2′-fluoro-4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.25 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.087 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.074 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.14 g, 49%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H) 1.07 (s, 6H)1.20-1.37 (m, 2H) 1.48-1.76 (m, 4H) 2.05-2.16 (m, 2H) 2.52-2.66 (m, 2H)2.89-2.98 (m, 2H) 3.20 (s, 2H) 3.26-3.37 (m, 1H) 3.97 (s, 2H) 4.23 (s,1H) 4.91 (t, J=12.2 Hz, 1H) 7.11-7.18 (m, 2H) 7.25 (t, J=8.0 Hz, 1H)7.45-7.51 (m, 1H) 7.57-7.65 (m, 1H) 7.67-7.74 (m, 2H) 8.18 (s, 1H) 12.59(br. s., 1H)

Example 2327-butyl-4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.41 g), sodium hydrogencarbonate (0.67 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-({7-butyl-4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.22 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.077 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.065 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.15 g, 55%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (t, J=7.2 Hz, 3H) 1.07 (s, 6H)1.21-1.56 (m, 6H) 1.64-1.76 (m, 2H) 2.06-2.16 (m, 2H), 2.52-2.65 (m, 2H)2.89-3.00 (m, 2H) 3.20 (s, 2H) 3.26-3.36 (m, 1H) 3.95 (s, 2H) 4.23 (s,1H) 4.85-4.98 (m, 1H) 7.19-7.25 (m, 2H) 7.26-7.32 (m, 2H) 7.46-7.58 (m,2H) 7.62-7.71 (m, 2H) 8.18 (s, 1H) 12.39 (br. s., 1H)

Example 2336-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.34 g), sodium hydrogencarbonate (0.54 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,3′-fluoro-4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.18 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.063 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.053 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.13 g, 64%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H) 1.07 (s, 6H)1.19-1.35 (m, 2H) 1.49-1.73 (m, 4H) 2.05-2.16 (m, 2H) 2.52-2.66 (m, 2H)2.88-2.99 (m, 2H) 3.20 (s, 2H) 3.25-3.36 (m, 1H) 3.94 (s, 2H) 4.22 (s,1H) 4.89 (t, J=12.2 Hz, 1H) 6.99 (dd, J=7.9, 1.7 Hz, 1H) 7.12-7.29 (m,2H) 7.51-7.62 (m, 2H) 7.64-7.75 (m, 2H) 8.19 (s, 1H) 12.45 (br. s., 1H)

Example 2344-{trans-4-[2-(methylsulfanyl)ethoxy]cyclohexyl}-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.39 g), sodium hydrogencarbonate (0.62 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-[(4-{trans-4-[2-(methylsulfanyl)ethoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.2 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.072 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.061 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.13 g, 59%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H) 1.20-1.37 (m, 2H)1.45-1.76 (m, 4H) 2.05-2.16 (m, 5H) 2.52-2.65 (m, 4H) 2.88-2.99 (m, 2H)3.32-3.41 (m, 1H) 3.61 (t, J=6.8 Hz, 2H) 3.95 (s, 2H) 4.91 (t, J=12.4Hz, 1H) 7.18-7.25 (m, 2H) 7.26-7.34 (m, 2H) 7.47-7.58 (m, 2H) 7.61-7.72(m, 2H) 8.18 (s, 1H) 12.38 (s, 1H)

Example 2354-{trans-4-[2-(methylsulfonyl)ethoxy]cyclohexyl}-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4-{trans-4-[2-(methylsulfanyl)ethoxy]cyclohexyl}-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.08 g), m-chloroperbenzoic acid (0.082 g) and acetonitrile (5 mL) wasstirred at room temperature for 1 hr. The reaction mixture was dilutedwith ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless amorphous solid (0.047 g, 56%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H) 1.22-1.40 (m, 2H)1.46-1.61 (m, 2H) 1.66-1.76 (m, 2H) 2.07-2.18 (m, 2H) 2.52-2.68 (m, 2H)2.88-2.97 (m, 2H) 2.99 (s, 3H) 3.32-3.45 (m, 3H) 3.82 (t, J=5.7 Hz, 2H)3.96 (s, 2H) 4.92 (t, J=12.4 Hz, 1H) 7.18-7.73 (m, 2H) 7.28-7.34 (m, 2H)7.46-7.58 (m, 2H) 7.62-7.73 (m, 2H) 8.18 (s, 1H) 12.38 (s, 1H)

Example 2367-butyl-4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

7-Butyl-4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.096 g) was suspended in isopropyl alcohol (3 mL), 1N potassiumhydroxide solution (0.16 mL) was added, and the solvent was evaporatedunder reduced pressure. The residue was solidified with diisopropylether to give the title compound as a colorless solid (0.071 g, 70%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.86 (t, J=7.3 Hz, 3H) 1.07 (s, 6H)1.20-1.58 (m, 6H) 1.65-1.79 (m, 2H) 2.05-2.16 (m, 2H) 2.51-2.66 (m, 2H)2.91-3.01 (m, 2H) 3.20 (s, 2H) 3.25-3.32 (m, 1H) 3.91 (s, 2H) 4.25 (br.s., 1H) 4.92 (t, J=12.3 Hz, 1H) 7.13-7.50 (m, 8H) 8.17 (s, 1H)

Example 2376-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

6-{[3-Fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.091 g) was suspended in isopropyl alcohol (3 mL), 1N potassiumhydroxide solution (0.15 mL) was added, and the solvent was evaporatedunder reduced pressure. The residue was solidified with diisopropylether to give the title compound as a colorless solid (0.075 g, 78%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.3 Hz, 3H) 1.07 (s, 6H)1.20-1.37 (m, 2H) 1.52-1.79 (m, 4H) 2.03-2.16 (m, 2H) 2.52-2.65 (m, 2H)2.89-2.99 (m, 2H) 3.20 (s, 2H) 3.25-3.31 (m, 1H) 3.90 (s, 2H) 4.24 (s,1H) 4.83-4.97 (m, 1H) 6.79-7.17 (m, 3H) 7.28-7.53 (m, 4H) 8.18 (s, 1H)

Example 2386-{[2-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

6-{[2-Fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.091 g) was suspended in isopropyl alcohol (3 mL), 1N potassiumhydroxide solution (0.15 mL) was added, and the solvent was evaporatedunder reduced pressure. The residue was solidified with diisopropylether to give the title compound as a colorless solid (0.075 g, 78%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.96 (t, J=7.3 Hz, 3H) 1.07 (s, 6H)1.22-1.35 (m, 2H) 1.53-1.77 (m, 4H) 2.03-2.15 (m, 2H) 2.52-2.67 (m, 2H)2.89-3.01 (m, 2H) 3.20 (s, 2H) 3.25-3.32 (m, 1H) 3.94 (s, 2H) 4.24 (s,1H) 4.92 (t, J=12.2 Hz, 1H) 6.79-7.22 (m, 4H) 7.36-7.43 (m, 2H)7.67-7.74 (m, 1H) 8.18 (s, 1H)

Example 2391,1-dimethyl-2-({trans-4-[2-methyl-5-oxo-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl]cyclohexyl}oxy)ethylacetate

A mixture of hydroxylammonium chloride (0.18 g), sodium hydrogencarbonate (0.28 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-1,1-dimethylethylacetate (0.1 g) was added, and the mixture was stirred at 90° C. for 16hr. The reaction mixture was diluted with ethyl acetate, washed withwater and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was dissolved in tetrahydrofuran (5 mL).N,N′-Carbonyldiimidazole (0.033 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.028 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.064 g, 58%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.4 Hz, 3H) 1.20-1.39 (m, 8H)1.44-1.73 (m, 4H) 1.93 (s, 3H) 2.03-2.14 (m, 2H) 2.35 (s, 3H) 2.52-2.65(m, 2H) 2.83-2.93 (m, 2H) 3.24-3.31 (m, 1H) 3.57 (s, 2H) 3.93 (s, 2H)4.87 (t, J=12.1 Hz, 1H) 7.18-7.32 (m, 4H) 7.46-7.59 (m, 2H) 7.60-7.72(m, 2H) 12.37 (br. s., 1H)

Example 2407-butyl-4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.59 g), sodium hydrogencarbonate (0.95 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-({7-butyl-4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-2-methyl-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.33 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.11 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.093 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.16 g, 43%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.79-0.87 (m, 3H) 0.97-1.10 (m, 9H)1.21-1.52 (m, 6H) 1.61-1.72 (m, 2H) 1.99-2.14 (m, 2H) 2.35 (s, 3H)2.52-2.65 (m, 2H) 2.85-2.94 (m, 2H) 3.21-3.42 (m, 6H) 3.92 (s, 2H) 4.06(s, 1H) 4.80-4.92 (m, 1H) 7.18-7.31 (m, 4H) 7.46-7.58 (m, 2H) 7.62-7.72(m, 2H) 12.39 (br. s., 1H)

Example 2416-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-2-methyl-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.48 g), sodium hydrogencarbonate (0.77 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,3′-fluoro-4′-({4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.27 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.09 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.076 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.19 g, 64%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H) 0.98-1.09 (m, 9H)1.20-1.36 (m, 2H) 1.48-1.72 (m, 4H) 2.00-2.15 (m, 2H) 2.36 (s, 3H)2.52-2.64 (m, 2H) 2.82-2.93 (m, 2H) 3.25 (q, J=6.2 Hz, 1H) 3.32-3.42 (m,1H) 3.91 (s, 2H) 4.05 (s, 1H) 4.76-4.89 (m, 1H) 6.98 (dd, J=7.9, 1.7 Hz,1H) 7.12-7.25 (m, 2H) 7.51-7.62 (m, 2H) 7.64-7.74 (m, 2H) 12.45 (br. s.,1H)

Example 2427-butyl-4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

7-Butyl-4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.1 g) was suspended in isopropyl alcohol (5 mL), 1N potassiumhydroxide solution (0.16 mL) was added, and the solvent was evaporatedunder reduced pressure. The residue was solidified with diisopropylether to give the title compound as a colorless solid (0.075 g, 70%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.85 (t, J=7.3 Hz, 3H) 0.96-1.10 (m, 9H)1.16-1.73 (m, 8H) 1.96-2.15 (m, 2H) 2.35 (s, 3H) 2.52-2.65 (m, 2H)2.85-2.96 (m, 2H) 3.25 (q, J=6.2 Hz, 1H) 3.34-3.44 (m, 1H) 3.87 (s, 2H)4.06 (s, 1H) 4.79-4.92 (m, 1H) 7.11-7.50 (m, 8H)

Example 2436-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-2-methyl-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

6-{[3-Fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-2-methyl-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.16 g) was suspended in isopropyl alcohol (5 mL), 1N potassiumhydroxide solution (0.25 mL) was added, and the solvent was evaporatedunder reduced pressure. The residue was solidified with diisopropylether to give the title compound as a colorless solid (0.12 g, 69%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89-1.10 (m, 12H) 1.15-1.37 (m, 2H)1.50-1.72 (m, 4H) 1.95-2.13 (m, 2H) 2.36 (s, 3H) 2.52-2.65 (m, 2H)2.83-2.93 (m, 2H) 3.25 (q, J=6.2 Hz, 1H) 3.34-3.43 (m, 1H) 3.87 (s, 2H)4.06 (s, 1H) 4.84 (t, J=10.3 Hz, 1H) 6.97-7.14 (m, 3H) 7.28-7.54 (m, 4H)

Example 2442-({trans-4-[5-oxo-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl]cyclohexyl}oxy)propanenitrile

A mixture of hydroxylammonium chloride (0.58 g), sodium hydrogencarbonate (0.93 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]propanamide(0.3 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.11 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.092 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The obtained residue was dissolved in tetrahydrofuran(10 mL), pyridine (0.18 mL) and trifluoroacetic acid anhydride (0.15 mL)were added at 0° C., and the mixture was stirred for 30 min. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas colorless crystals (0.15 g, 47%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H) 1.22-1.60 (m, 7H)1.67-1.79 (m, 2H) 2.07-2.22 (m, 2H) 2.55-2.69 (m, 2H) 2.88-2.99 (m, 2H)3.52-3.66 (m, 1H) 3.96 (s, 2H) 4.71 (q, J=6.8 Hz, 1H) 4.85-4.99 (m, 1H)7.19-7.25 (m, 2H) 7.28-7.34 (m, 2H) 7.47-7.58 (m, 2H) 7.61-7.72 (m, 2H)8.19 (s, 1H) 12.38 (s, 1H)

Example 2456-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-{trans-4-[(4-hydroxy-4-methyltetrahydrofuran-3-yl)oxy]cyclohexyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.13 g), sodium hydrogencarbonate (0.22 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,3′-fluoro-4′-[(4-{trans-4-[(4-hydroxy-4-methyltetrahydrofuran-3-yl)oxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.077 g) was added, and the mixture was stirred at 90° C. for 16 hr.The reaction mixture was diluted with ethyl acetate, washed with waterand then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was dissolved in tetrahydrofuran (5 mL).N,N′-Carbonyldiimidazole (0.025 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.022 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.029 g, 34%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.4 Hz, 3H) 1.10-1.75 (m, 9H)2.01-2.25 (m, 2H) 2.52-2.67 (m, 2H) 2.87-3.00 (m, 2H) 3.41-3.56 (m, 4H)3.71 (t, J=5.5 Hz, 1H) 3.89-3.98 (m, 3H) 4.25 (s, 1H) 4.89 (t, J=12.1Hz, 1H) 6.99 (dd, J=8.0, 1.9 Hz, 1H) 7.12-7.28 (m, 2H) 7.51-7.74 (m, 4H)8.19 (s, 1H) 12.46 (br. s., 1H)

Example 2466-{[4′-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-2-methyl-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.43 g), sodium hydrogencarbonate (0.69 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4-fluoro-4′-({4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.24 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.079 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.067 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.15 g, 56%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91 (t, J=7.2 Hz, 3H) 0.97-1.10 (m, 9H)1.20-1.73 (m, 6H) 1.97-2.17 (m, 2H) 2.35 (s, 3H) 2.53-2.66 (m, 2H)2.83-2.93 (m, 2H) 3.20-3.44 (m, 2 H) 3.92 (s, 2H) 4.05 (s, 1H) 4.85 (t,J=11.9 Hz, 1H) 7.16-7.22 (m, 2H) 7.25-7.31 (m, 2H) 7.51-7.62 (m, 3H)12.50 (s, 1H)

Example 247(+)-6-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(retention time: short)

A mixture of hydroxylammonium chloride (7.5 g), sodium hydrogencarbonate (12 g) and dimethyl sulfoxide (50 mL) was stirred at 40° C.for 30 min.3′-Fluoro-4′-({4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(retention time: short, 4 g) was added, and the mixture was stirred at90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate,washed with water and then with brine, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The resulting residuewas dissolved in tetrahydrofuran (100 mL). N,N′-Carbonyldiimidazole (1.4g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.2 mL) were successivelyadded, and the mixture was stirred at room temperature for 2 hr. Thereaction mixture was diluted with ethyl acetate, washed with saturatedaqueous potassium hydrogensulfate solution and then with brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(4 g, 91%, >99% ee).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H), 0.98-1.10 (m, 9H),1.22-1.38 (m, 2H), 1.51-1.72 (m, 4H), 2.00-2.13 (m, 2H), 2.52-2.65 (m,2H), 2.88-2.98 (m, 2H), 3.24 (q, J=6.2 Hz, 1H), 3.33-3.43 (m, 1H), 3.94(s, 2H), 4.06 (s, 1H), 4.80-4.94 (m, 1H), 6.99 (dd, J=7.9, 1.7 Hz, 1H),7.12-7.28 (m, 2H), 7.51-7.61 (m, 2H), 7.64-7.73 (m, 2H), 8.19 (s, 1H),12.46 (br. s., 1H)

Analysis of Enantiomeric Excess

column: CHIRALPAK AD-H (CG075) 4.6 mm ID×250 mL

mobile phase: CO₂/MeOH=600/400 (v/v)

flow rate: 2.35 ml/min

temperature: 35° C.

detection: UV220 nm

concentration: 0.5 mg/ml

injection volume: 5 μl

retention time: 6.59 min

specific optical rotation [α]²⁵ _(D)+24.0° (c=0.2045, in methanol)

Example 2486-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(retention time: long)

A mixture of hydroxylammonium chloride (0.37 g), sodium hydrogencarbonate (0.6 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,3′-fluoro-4′-({4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(retention time: long, 0.2 g) obtained in Reference Example 202 wasadded, and the mixture was stirred at 90° C. for 16 hr. The reactionmixture was diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was dissolved intetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.069 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.058 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.19 g, >99% ee).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89-1.10 (m, 12H) 1.20-1.73 (m, 6H)1.94-2.14 (m, 2H) 2.52-2.67 (m, 2H) 2.88-2.98 (m, 2H) 3.24 (q, J=6.2 Hz,1H) 3.33-3.43 (m, 1H) 3.94 (s, 2H) 4.05 (s, 1H) 4.80-4.95 (m, 1H) 6.99(dd, J=7.9, 1.7 Hz, 1H) 7.13-7.28 (m, 2H) 7.51-7.73 (m, 4H) 8.19 (s, 1H)12.45 (br. s., 1H)

Analysis of Enantiomeric Excess

column: CHIRALPAK AD-H (CG075) 4.6 mm ID×250 mL

mobile phase: CO₂/MeOH=600/400 (v/v)

flow rate: 2.35 ml/min

temperature: 35° C.

detection: UV220 nm

concentration: 0.5 mg/ml

injection volume: 5 μl

retention time: 10.01 min

Example 2492-({trans-4-[6-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl]cyclohexyl}oxy)propanenitrile

A mixture of hydroxylammonium chloride (0.68 g), sodium hydrogencarbonate (1.1 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,2-[(trans-4-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]propanamide(0.37 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.13 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The obtained residue was dissolved in tetrahydrofuran(10 mL), pyridine (0.21 mL) and trifluoroacetic acid anhydride (0.18 mL)were added at 0° C., and the mixture was stirred for 30 min. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas colorless crystals (0.11 g, 28%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.4 Hz, 3H) 1.20-1.77 (m, 9H)2.05-2.20 (m, 2H) 2.37 (s, 3H) 2.42-2.58 (m, 2H) 2.83-2.93 (m, 2H)3.50-3.63 (m, 1H) 3.92 (s, 2H) 4.71 (q, J=6.6 Hz, 1H) 4.80-4.94 (m, 1H)6.98 (dd, J=8.0, 1.5 Hz, 1H) 7.11-7.27 (m, 2H) 7.51-7.62 (m, 2H)7.64-7.74 (m, 2H) 12.45 (s, 1H)

Example 250(+)-6-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt (retention time: short)

To a solution of(+)-6-[([3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(retention time: short, 4.3 g) in diethyl ether (200 mL) was added asolution of potassium 2-ethylhexanate (1.5 g) in ethyl acetate (15 mL)at 40° C. The reaction mixture was cooled to room temperature, andstirred for 4 hr. The precipitated crystals were collected byfiltration, washed with diisopropyl ether, and dried under reducedpressure at 140° C. to give the title compound (3.1 g, 68%, >99% ee).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91-1.10 (m, 12H), 1.17-1.40 (m, 2H),1.54-1.73 (m, 4H), 1.92-2.12 (m, 2H), 2.47-2.64 (m, 2H), 2.88-2.99 (m,2H), 3.24 (q, J=6.4 Hz, 1H), 3.29-3.41 (m, 1H), 3.90 (s, 2H), 4.05 (s,1H), 4.80-4.95 (m, 1H), 6.98-7.17 (m, 3H), 7.29-7.53 (m, 4H), 8.18 (s,1H)

Analysis of Enantiomeric Excess

column: CHIRALPAK AD-H (LA145) 4.6 mm ID×250 mL

mobile phase: CO₂/MeOH=650/350 (v/v)

flow rate: 2.35 ml/min

pressure: 100 bar

temperature: 35° C.

detection: UV220 nm

concentration: 0.5 mg/ml

injection volume: 5 μl

retention time: 7.3 min

specific optical rotation [α]²⁵ _(D)+14.2° (c=1.0055, in methanol)

melting point 154° C.

Crystal form was characterized by powder X ray diffraction pattern usingCuKα X-ray radiation, having peaks selected from a list consisting of:

diffraction angle: 2θ (°) interplanar distance: d value (Å) 4.4 20.06585.82 15.1728 6.42 13.7561 8.1 10.9063 13.38 6.612 14.38 6.1544 15.345.7713 18.78 4.7212 20.2 4.3924

Example 2516-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt (retention time: long)

6-{[3-Fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(retention time: long, 0.064 g) was suspended in isopropyl alcohol (3mL), 1N potassium hydroxide solution (0.1 mL) was added, and the solventwas evaporated under reduced pressure. The residue was solidified withdiisopropyl ether to give the title compound as a colorless solid (0.052g, 76%>99% ee).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90-1.11 (m, 15H) 1.16-1.40 (m, 2H)1.53-1.74 (m, 4H) 1.94-2.14 (m, 2H) 2.53-2.66 (m, 2H) 2.88-2.99 (m, 2H)3.19-3.43 (m, 2H) 3.90 (s, 2H) 4.05 (s, 1H) 4.80-4.96 (m, 1H) 6.97-7.17(m, 3H) 7.28-7.53 (m, 4H) 8.18 (s, 1H)

Analysis of Enantiomeric Excess

column: CHIRALPAK AD-H (CG075) 4.6 mm ID×250 mL

mobile phase: CO₂/MeOH=650/350 (v/v)

flow rate: 2.35 ml/min

temperature: 35° C.

detection: UV220 nm

concentration: 0.5 mg/ml

injection volume: 5 μl

retention time: 9.7 min

Example 2526-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-{trans-4-[(1-hydroxycyclobutyl)methoxy]cyclohexyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.34 g), sodium hydrogencarbonate (0.55 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,3′-fluoro-4′-[(4-{trans-4-[(1-hydroxycyclobutyl)methoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.19 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.064 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.054 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.13 g, 60%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.4 Hz, 3H) 1.21-1.75 (m, 8H)1.79-2.04 (m, 4H) 2.09-2.20 (m, 2H) 2.59 (br. s., 2H) 2.89-2.97 (m, 2H)3.28-3.41 (m, 3H) 3.94 (s, 2H) 4.80-4.95 (m, 2H) 6.95-7.02 (m, 1H)7.12-7.28 (m, 2H) 7.51-7.62 (m, 2H) 7.63-7.73 (m, 2H) 8.19 (s, 1H) 12.45(br. s., 1H)

Example 2534-(cis-3-hydroxycyclobutyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4′-{[4-(cis-3-hydroxycyclobutyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.28 g), tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.22 mL),2,6-lutidine (0.11 mL) and tetrahydrofuran (10 mL) was stirred at 0° C.for 3 hr. The reaction mixture was diluted with ethyl acetate, washedwith water and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The residue obtained by silica gel column chromatography was dissolvedin dimethyl sulfoxide (5 mL), and added to a mixture of hydroxylammoniumchloride (0.66 g), sodium hydrogen carbonate (1.1 g) and dimethylsulfoxide (5 mL), which had been stirred in advance at 40° C. for 30min. The reaction mixture was stirred at 90° C. for 16 hr, diluted withethyl acetate, washed with water and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was dissolved in tetrahydrofuran (5mL). N,N′-Carbonyldiimidazole (0.13 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.1 mL) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was dissolved in tetrahydrofuran (15 mL).Tetrabutylammonium bromide (1.0 M tetrahydrofuran solution, 1.6 mL) wasadded, and the mixture was stirred at room temperature for 3 hr. Thereaction mixture was extracted with 1 N hydrochloric acid and ethylacetate, and the ethyl acetate layer was washed with saturated brine andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.18 g, 58%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H) 1.45-1.66 (m, 2H)2.52-2.63 (m, 2H) 2.88-3.03 (m, 4H) 3.86-4.02 (m, 3H) 4.76-4.91 (m, 1H)5.23 (q, J=5.8 Hz, 1H) 7.20-7.34 (m, 4H) 7.47-7.59 (m, 2H) 7.62-7.73 (m,2H) 8.21 (s, 1H) 12.39 (s, 1H)

Example 2544-[cis-3-(2-hydroxy-2-methylpropoxy)cyclobutyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.31 g), sodium hydrogencarbonate (0.51 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-({4-[cis-3-(2-hydroxy-2-methylpropoxy)cyclobutyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.15 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.059 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.05 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.069 g, 40%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H) 1.09 (s, 6H)1.47-1.63 (m, 2H) 2.54-2.66 (m, 2H) 2.89-3.08 (m, 4H) 3.11 (s, 2H)3.76-3.88 (m, 1H) 3.95 (s, 2H) 4.31 (s, 1H) 4.84-5.00 (m, 1H) 7.19-7.34(m, 4H) 7.47-7.58 (m, 2H) 7.62-7.72 (m, 2H) 8.20 (s, 1H) 12.38 (br. s.,1H)

Example 2554-(3-oxocyclobutyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4-(cis-3-hydroxycyclobutyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.1 g), Dess-Martin reagent (0.13 g) and acetonitrile (5 mL) wasstirred at room temperature for 2 hr. Saturated aqueous sodium hydrogencarbonate solution and sodium thiosulfate were added to the reactionmixture, and the mixture was stirred at room temperature for 2 hr, andextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography to give the title compound as acolorless amorphous solid (0.077 g, 78%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H) 1.47-1.64 (m, 2H)2.89-3.00 (m, 2H) 3.42-3.55 (m, 2H) 3.76-3.89 (m, 2H) 3.98 (s, 2H)5.74-5.88 (m, 1H) 7.19-7.26 (m, 2H) 7.30-7.36 (m, 2H) 7.47-7.58 (m, 2H)7.62-7.72 (m, 2H) 8.22 (s, 1H) 12.38 (br. s., 1H)

Example 2564-[trans-3-(2-hydroxy-2-methylpropoxy)cyclobutyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.11 g), sodium hydrogencarbonate (0.18 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-({4-[trans-3-(2-hydroxy-2-methylpropoxy)cyclobutyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.056 g) was added, and the mixture was stirred at 90° C. for 16 hr.The reaction mixture was diluted with ethyl acetate, washed with waterand then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was dissolved in tetrahydrofuran (5 mL).N,N′-Carbonyldiimidazole (0.021 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.018 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.03 g,48%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H) 1.11 (s, 6H)1.47-1.61 (m, 2H) 2.23-2.36 (m, 2H) 2.90-3.00 (m, 2H) 3.09 (s, 2H)3.12-3.25 (m, 2H) 3.95 (s, 2H) 4.23-4.36 (m, 2H) 5.62-5.75 (m, 1H)7.18-7.26 (m, 2H) 7.27-7.35 (m, 2H) 7.47-7.59 (m, 2H) 7.62-7.72 (m, 2H)8.21 (s, 1H) 12.38 (s, 1H)

Example 2574-(trans-3-hydroxycyclobutyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4′-{[4-(trans-3-hydroxycyclobutyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.13 g), tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.14 mL),2,6-lutidine (0.069 mL) and tetrahydrofuran (5 mL) was stirred at 0° C.for 3 hr. The reaction mixture was diluted with ethyl acetate, washedwith water and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The residue obtained by silica gel column chromatography was dissolvedin dimethyl sulfoxide (5 mL), and added to a mixture of hydroxylammoniumchloride (0.31 g), sodium hydrogen carbonate (0.5 g) and dimethylsulfoxide (5 mL), which had been stirred in advance at 40° C. for 30min. The reaction mixture was stirred at 90° C. for 16 hr, diluted withethyl acetate, washed with water and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was dissolved in tetrahydrofuran (5mL). N,N′-Carbonyldiimidazole (0.058 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.049 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was dissolved in tetrahydrofuran (5 mL).Tetrabutylammonium bromide (1.0 M tetrahydrofuran solution, 0.74 mL) wasadded, and the mixture was stirred at room temperature for 3 hr. Thereaction mixture was extracted with 1 N hydrochloric acid and ethylacetate, and the ethyl acetate layer was washed with saturated brine andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.06 g, 41%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.2 Hz, 3H) 1.46-1.62 (m, 2H)2.11-2.23 (m, 2H) 2.88-2.98 (m, 2H) 3.15-3.29 (m, 2H) 3.95 (s, 2H)4.44-4.54 (m, 1H) 5.11 (d, J=4.5 Hz, 1H) 5.69-5.84 (m, 1H) 7.19-7.34 (m,4H) 7.47-7.58 (m, 2H) 7.61-7.72 (m, 2H) 8.20 (s, 1H) 12.37 (s, 1H)

Example 2586-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-{trans-4-[(1-hydroxycyclobutyl)methoxy]cyclohexyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

6-{[3-Fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-{trans-4-[(1-hydroxycyclobutyl)methoxy]cyclohexyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(2 g) was suspended in isopropyl alcohol (30 mL), 4N potassium hydroxidesolution (0.78 mL) was added, and the solvent was evaporated underreduced pressure. The residue was solidified with diisopropyl ether togive the title compound as a colorless solid (2 g, 95%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.35 Hz, 3H) 1.20-1.76 (m, 8H)1.80-2.18 (m, 6H) 2.52-2.67 (m, 2H) 2.89-2.99 (m, 2H) 3.29-3.42 (m, 3H)3.90 (s, 2H) 4.80-4.98 (m, 2H) 6.98-7.17 (m, 3H) 7.28-7.54 (m, 4H) 8.18(s, 1H)

Example 2594-[trans-3-(2-ethyl-2-hydroxybutoxy)cyclobutyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.12 g), sodium hydrogencarbonate (0.19 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-({4-[trans-3-(2-ethyl-2-hydroxybutoxy)cyclobutyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.06 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.022 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.018 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.052g, 79%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.82 (t, J=7.19 Hz, 6H) 0.92 (t, J=7.38 Hz,3H) 1.42 (q, J=7.57 Hz, 4H) 1.47-1.63 (m, 2H) 2.23-2.36 (m, 2H)2.89-2.98 (m, 2H) 3.09-3.25 (m, 4H) 3.95 (s, 2H) 4.01 (s, 1H) 4.26 (t,J=6.82 Hz, 1H) 5.60-5.74 (m, 1H) 7.19-7.25 (m, 2H) 7.28-7.34 (m, 2H)7.47-7.58 (m, 2H) 7.62-7.72 (m, 2H) 8.21 (s, 1H) 12.37 (br. s., 1H)

Example 2604-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-6-({5-[2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl]thiophen-2-yl}methyl)-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.23 g), sodium hydrogencarbonate (0.37) and dimethyl sulfoxide (5 mL) was stirred at 40° C. for30 min,2-[5-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)thiophen-2-yl]benzonitrile(0.12 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.043 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.036 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.05 g, 38%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.98 (t, J=7.3 Hz, 3H) 1.07 (6H, s)1.21-1.38 (m, 2H) 1.57-1.74 (m, 4H) 2.05-2.16 (m, 2H) 2.51-2.63 (m, 2H)2.93-3.03 (m, 2H) 3.20 (s, 2H) 3.26-3.32 (m, 1H) 4.08 (s, 2H) 4.26 (s,1H) 4.83-4.99 (m, 1H) 6.93-6.99 (m, 2H) 7.45-7.54 (m, 1H) 7.57-7.67 (m,3H) 8.20 (s, 1H) 12.52 (s, 1H)

Example 2614-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-6-({5-[2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl]thiophen-2-yl}methyl)-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

4-[trans-4-(2-Hydroxy-2-methylpropoxy)cyclohexyl]-6-({5-[2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl]thiophen-2-yl}methyl)-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.075 g) was suspended in isopropyl alcohol (3 mL), 1N potassiumhydroxide solution (0.12 mL) was added, and the solvent was evaporatedunder reduced pressure. The residue was solidified with diisopropylether to give the title compound as a colorless solid (0.06 g, 75%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.99 (t, J=7.3 Hz, 3H) 1.07 (s, 6H)1.20-1.38 (m, 2H) 1.59-1.74 (m, 4H) 2.05-2.16 (m, 2H) 2.52-2.66 (m, 2H)2.94-3.02 (m, 2H) 3.20 (s, 2H) 3.25-3.31 (m, 1H) 4.02 (s, 2H) 4.24(br.s., 1H) 4.90 (t, J=12.2 Hz, 1H) 6.79-6.83 (m, 1H) 6.91-6.95 (m, 1H)7.25-7.44 (m, 4H) 8.17 (s, 1H)

Example 2624-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-6-({6-[2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl]pyridin-3-yl}methyl)-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

Ethyl({trans-4-[6-{[6-(2-cyanophenyl)pyridin-3-yl]methyl}-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl]cyclohexyl}oxy)acetate(0.06 g) was dissolved in tetrahydrofuran (5 mL), and methylmagnesiumbromide (1.0 M tetrahydrofuran solution, 0.32 mL) was added at roomtemperature. The reaction mixture was stirred for 2 hr, saturatedaqueous ammonium chloride solution was added, and the mixture wasextracted with ethyl acetate. The obtained ethyl acetate layer waswashed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The obtained residuewas dissolved in dimethyl sulfoxide (5 mL), and the mixture was added toa mixture of hydroxylammonium chloride (0.11 g), sodium hydrogencarbonate (0.18 g) and dimethyl sulfoxide (5 mL), which had been stirredin advance at 40° C. for 30 min. The reaction mixture was stirred at 90°C. for 16 hr, diluted with ethyl acetate, washed with water and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography and dissolved intetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.021 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.018 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.011 g,17%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.09 (t, J=7.3 Hz, 3H) 1.20 (s, 6H)1.37-1.53 (m, 2H) 1.70-1.84 (m, 4H) 2.14-2.25 (m, 2H) 2.61-2.77 (m, 2H)3.02-3.11 (m, 2H) 3.30 (s, 2H) 3.38-3.51 (m, 1H) 4.03 (s, 2H) 4.98-5.13(m, 1H) 7.37-7.61 (m, 4H) 7.71-7.81 (m, 2H) 7.93 (s, 1H) 8.49 (d, 1H)

Example 263

5-butyl-8-[4-(1-methylethoxy)phenyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[4,3-a]pyrimidin-7(8H)-one

A mixture of hydroxylammonium chloride (0.66 g), sodium hydrogencarbonate (1.1 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[5-butyl-8-[4-(1-methylethoxyphenyl)-7-oxo-7,8-dihydro[1,2,4]triazolo[4,3-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.33 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.12 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.1 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.16 g, 43%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.81-0.91 (m, 3H) 1.31 (d, J=6.0 Hz, 6H)1.36-1.52 (m, 4H) 2.95 (t, J=6.2 Hz, 2H) 3.95 (s, 2H) 4.60-4.74 (m, 1H)6.98-7.08 (m, 2H) 7.19-7.26 (m, 2H) 7.30-7.39 (m, 4H) 7.45-7.59 (m, 2H)7.63-7.72 (m, 2H) 9.05 (s, 1H) 12.41 (s, 1H)

Example 2645-butyl-8-[4-(1-methylethoxy)phenyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[4,3-a]pyrimidin-7(8H)-onepotassium salt

5-Butyl-8-[4-(1-methylethoxy)phenyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[4,3-a]pyrimidin-7(8H)-one(0.14 g) was suspended in isopropyl alcohol (10 mL), 2N potassiumhydroxide solution (0.13 mL) was added, and the solvent was evaporatedunder reduced pressure. The residue was solidified with diisopropylether to give the title compound as a colorless solid (0.12 g, 75%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.87 (t, J=6.8 Hz, 3H) 1.31 (d, J=5.7 Hz,6H) 1.37-1.55 (m, 4H) 2.91-3.02 (m, 2H) 3.90 (s, 2H) 4.59-4.75 (m, 1H)7.03 (d, J=8.7 Hz, 2H) 7.16-7.50 (m, 10H) 9.02 (s, 1H)

Example 2652-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl-4-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.33 g), sodium hydrogencarbonate (0.54 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[2-methyl-5-oxo-7-propyl-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.15 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.062 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.053 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.079g, 47%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H) 1.42-1.65 (m, 4H)2.27 (s, 3H) 2.51-2.62 (m, 2H) 2.83-2.95 (m, 2H) 3.39-3.54 (m, 2H)3.86-4.04 (m, 4H) 4.76-4.94 (m, 1H) 6.20 (s, 1H) 7.17-7.32 (m, 4H) 7.53(dd, J=16.0, 7.7 Hz, 2H) 7.60-7.72 (m, 2H) 12.36 (s, 1H)

Example 2662-methyl-7-propyl-4-(tetrahydro-2H-pyran-4-yl)-6-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}pyrazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4′-{[2-methyl-5-oxo-7-propyl-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.1 g), dibutyltin oxide (0.011 g), azidotrimethylsilane (0.74 g) andtoluene (10 mL) was stirred at 110° C. for 48 hr. The reaction mixturewas diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as colorlesscrystals (0.035 g, 31%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.2 Hz, 3H) 1.41-1.63 (m, 4H)2.27 (s, 3H) 2.50-2.63 (m, 2H) 2.80-2.90 (m, 2H) 3.46 (t, J=11.0 Hz, 2H)3.86 (s, 2H) 3.97 (dd, J=10.6, 3.0 Hz, 2H) 4.75-4.92 (m, 1H) 6.20 (s,1H) 6.98 (d, J=8.0 Hz, 2H) 7.15 (d, J=8.3 Hz, 2H) 7.48-7.70 (m, 4H)16.20 (br. s., 1H)

Example 2673-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl-4-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.67 g), sodium hydrogencarbonate (1.1 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[3-methyl-5-oxo-7-propyl-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.3 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.13 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.2 g, 58%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (t, J=7.3 Hz, 3H) 1.39-1.54 (m, 2H)1.66-1.75 (m, 2H) 2.32 (s, 3H) 2.71-2.96 (m, 4H) 3.29-3.45 (m, 2H)3.87-4.01 (m, 4H) 4.39-4.54 (m, 1H) 7.19-7.31 (m, 4H) 7.47-7.58 (m, 2H)7.61-7.73 (m, 3H) 12.35 (br. s., 1H)

Example 2683-methyl-7-propyl-4-(tetrahydro-2H-pyran-4-yl)-6-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}pyrazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4′-{[3-methyl-5-oxo-7-propyl-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.33 g), dibutyltin oxide (0.088 g), azidotrimethylsilane (3.5 g) andtoluene (30 mL) was stirred at 110° C. for 48 hr. The reaction mixturewas diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as colorlesscrystals (0.15 g, 41%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.3 Hz, 3H) 1.35-1.53 (m, 2H)1.64-1.76 (m, 2H) 2.31 (s, 3H) 2.69-2.91 (m, 4H) 3.39 (t, J=11.4 Hz, 2H)3.85 (s, 2H) 3.97 (dd, J=11.1, 4.0 Hz, 2H) 4.45 (t, J=11.7 Hz, 1H) 6.99(d, J=8.3 Hz, 2H) 7.15 (d, J=8.1 Hz, 2H) 7.48-7.58 (m, 2H) 7.60-7.70 (m,3H)

Example 2696-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl-4-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.69 g), sodium hydrogencarbonate (1.1 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[5-oxo-7-propyl-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.3 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.13 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.18 g,52%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.2 Hz, 3H) 1.43-1.67 (m, 4H)2.52-2.66 (m, 2H) 2.89-3.02 (m, 2H) 3.48 (t, J=11.2 Hz, 2H) 3.92-4.03(m, 4H) 4.88 (t, J=11.4 Hz, 1H) 6.38 (d, J=1.9 Hz, 1H) 7.19-7.25 (m, 2H)7.27-7.33 (m, 2H) 7.53 (dd, J=16.1, 7.8 Hz, 2H) 7.63-7.72 (m, 2H) 7.84(d, J=2.3 Hz, 1H) 12.36 (s, 1H)

Example 2707-propyl-4-(tetrahydro-2H-pyran-4-yl)-6-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}pyrazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4′-{[5-oxo-7-propyl-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.33 g), dibutyltin oxide (0.083 g), azidotrimethylsilane (2.3 g) andtoluene (20 mL) was stirred at 110° C. for 48 hr. The reaction mixturewas diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.15 g, 46%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91 (t, J=7.4 Hz, 3H) 1.41-1.65 (m, 4H)2.52-2.63 (m, 2H) 2.87-2.97 (m, 2H) 3.47 (t, J=11.2 Hz, 2H) 3.89 (s, 2H)3.94-4.02 (m, 2H) 4.86 (t, J=12.1 Hz, 1H) 6.37 (d, J=2.3 Hz, 1H) 6.99(d, J=8.3 Hz, 2H) 7.17 (d, J=8.0 Hz, 2H) 7.53 (dd, J=13.1, 7.0 Hz, 2H)7.59-7.70 (m, 2H) 7.83 (d, J=1.9 Hz, 1H)

Example 2714-[trans-4-(4-methoxyphenoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

To a solution of4′-{[4-(cis-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.46 g), 4-methoxyphenol (0.27 g) and triphenylphosphine (0.28 g) intetrahydrofuran (1.0 mL) was added dropwise a solution of diisopropylazodicarboxylate (0.58 mL, 1.9 M toluene solution) in tetrahydrofuran(1.5 mL) at 0° C., and the mixture was stirred at room temperature for 4hr. The reaction mixture was added to 1 M hydrochloric acid, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure. A solution of the residueobtained by purification by silica gel column chromatography in dimethylsulfoxide (2 mL) was added to a mixture of hydroxylammonium chloride(1.0 g), sodium hydrogen carbonate (1.7 g), and dimethyl sulfoxide (3mL), which had been stirred at 40° C. for 30 min in advance, and themixture was stirred at 90° C. for 15 hr. Ethyl acetate and water wereadded to the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was dissolved in tetrahydrofuran (5mL). N,N′-Carbonyldiimidazole (0.19 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.18 mL) were added, and the mixturewas stirred at room temperature for 40 min. Ethyl acetate and water wereadded to the reaction mixture, and the mixture was acidified with 1 Mhydrochloric acid and extracted with ethyl acetate. The organic layerwas washed with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.24 g, 39%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.10 (t, J=7.35 Hz, 3H) 1.51-1.90 (m,6H) 2.19-2.35 (m, 2H) 2.66-2.85 (m, 2H) 2.98-3.14 (m, 2H) 3.77 (s, 3H)3.99 (s, 2H) 4.16-4.31 (m, 1H) 4.98-5.18 (m, 1H) 6.73-6.94 (m, 4H)7.23-7.31 (m, 2H) 7.32-7.44 (m, 3H) 7.45-7.54 (m, 1H) 7.56-7.66 (m, 1H)7.80-7.90 (m, 1H) 7.93 (s, 1H)

Example 2724-[cis-4-(4-methoxyphenoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

To a solution of4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.46 g), 4-methoxyphenol (0.27 g) and triphenylphosphine (0.28 g) intetrahydrofuran (1.0 mL) was added dropwise a solution of diisopropylazodicarboxylate (0.58 mL, 1.9 M toluene solution) in tetrahydrofuran(1.5 mL) at 0° C., and the mixture was stirred at room temperature for5.5 hr. The reaction mixture was added to 1 M hydrochloric acid, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure. A solution of the residueobtained by purification by silica gel column chromatography in dimethylsulfoxide (2 mL) was added to a mixture of hydroxylammonium chloride(1.0 g), sodium hydrogen carbonate (1.7 g), and dimethyl sulfoxide (3mL), which had been stirred at 40° C. for 30 min in advance, and themixture was stirred at 90° C. for 15 hr. Ethyl acetate and water wereadded to the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was dissolved in tetrahydrofuran (5mL). N,N′-Carbonyldiimidazole (0.19 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.18 mL) were added, and the mixturewas stirred at room temperature for 40 min. Ethyl acetate and water wereadded to the reaction mixture, and the mixture was acidified with 1 Mhydrochloric acid and extracted with ethyl acetate. The organic layerwas washed with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.25 g, 39%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.10 (t, J=7.35 Hz, 3H) 1.51-1.87 (m,6H) 2.12-2.28 (m, 2H) 2.99-3.19 (m, 4H) 3.77 (s, 3H) 4.01 (s, 2H)4.41-4.52 (m, 1H) 4.99-5.17 (m, 1H) 6.77-6.88 (m, 2H) 6.93-7.04 (m, 2H)7.23-7.31 (m, 2H) 7.32-7.44 (m, 3H) 7.45-7.54 (m, 1H) 7.56-7.65 (m, 1H)7.87 (dd, J=7.72, 1.13 Hz, 1H) 7.97 (s, 1H)

Example 2734-[trans-4-(4-hydroxyphenoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.34 g), sodium hydrogencarbonate (0.55 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C.for 30 min,4′-({4-[trans-4-(4-{[tert-butyl(dimethyl)silyl]oxy}phenoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.22 g) was added, and the mixture was stirred at 90° C. for 23 hr.Ethyl acetate and water were added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.11 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.10 mL) were added, andthe mixture was stirred at room temperature for 3 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was acidifiedwith 1 M hydrochloric acid and extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.028 g, 14%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.19 Hz, 3H) 1.38-1.85 (m, 6H)2.12-2.26 (m, 2H) 2.58-2.81 (m, 2H) 2.85-3.03 (m, 2H) 3.97 (s, 2H)4.07-4.22 (m, 1H) 4.87-5.10 (m, 1H) 6.67 (d, J=8.71 Hz, 2H) 6.80 (d,J=9.09 Hz, 2H) 7.19-7.26 (m, 2H) 7.28-7.36 (m, 2H) 7.46-7.59 (m, 2H)7.61-7.77 (m, 2H) 8.20 (s, 1H) 8.92 (s, 1H) 12.38 (br. s., 1H)

Example 2744-[cis-4-(4-hydroxyphenoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.49 g), sodium hydrogencarbonate (0.79 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C.for 30 min,4′-({4-[cis-4-(4-{[tert-butyl(dimethyl)silyl]oxy}phenoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.31 g) was added, and the mixture was stirred at 90° C. for 23 hr.Ethyl acetate and water were added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (0.16 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 mL) were added, andthe mixture was stirred at room temperature for 3 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was acidifiedwith 1 M hydrochloric acid and extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.028 g, 9.8%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.19 Hz, 3H) 1.38-1.72 (m, 6H)2.00-2.08 (m, 2H) 2.83-3.05 (m, 4H) 3.99 (s, 2H) 4.37-4.48 (m, 1H)4.92-5.12 (m, 1H) 6.71 (d, J=8.71 Hz, 2H) 6.87 (d, J=8.71 Hz, 2H)7.21-7.28 (m, 2H) 7.28-7.39 (m, 2H) 7.46-7.60 (m, 2H) 7.61-7.74 (m, 2H)8.24 (s, 1H) 8.96 (br. s., 1H) 12.39 (br. s., 1H)

Example 2754-(cis-4-hydroxy-4-methylcyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.89 g), sodium hydrogencarbonate (1.4 g) and dimethyl sulfoxide (3.5 mL) was stirred at 40° C.for 30 min,4′-{[4-(cis-4-hydroxy-4-methylcyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.41 g) was added, and the mixture was stirred at 90° C. for 16 hr.Ethyl acetate and water were added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.13 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.12 mL) were added, andthe mixture was stirred at room temperature for 3 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was acidifiedwith 1 M hydrochloric acid and extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.14 g, 32%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.19 Hz, 3H) 1.15 (s, 3H)1.31-1.76 (m, 8H) 2.80-3.07 (m, 4H) 3.96 (s, 2H) 4.09 (s, 1H) 4.78-4.96(m, 1H) 7.19-7.26 (m, 2H) 7.28-7.36 (m, 2H) 7.46-7.60 (m, 2H) 7.62-7.74(m, 2H) 8.18 (s, 1H) 12.39 (br. s., 1H)

Example 2764-(trans-4-hydroxy-4-methylcyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.76 g), sodium hydrogencarbonate (1.2 g) and dimethyl sulfoxide (3.5 mL) was stirred at 40° C.for 30 min,4′-{[4-(trans-4-hydroxy-4-methylcyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.35 g) was added, and the mixture was stirred at 90° C. for 16 hr.Ethyl acetate and water were added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.11 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.10 mL) were added, andthe mixture was stirred at room temperature for 3 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was acidifiedwith 1 M hydrochloric acid and extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography andrecrystallized (ethyl acetate-hexane) to give the title compound as acolorless solid (0.14 g, 37%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.25 Hz, 3H) 1.28 (s, 3H)1.41-1.74 (m, 8H) 2.53-2.76 (m, 2H) 2.82-3.02 (m, 2H) 3.96 (s, 2H) 4.44(s, 1H) 4.79-5.01 (m, 1H) 7.18-7.25 (m, 2H) 7.27-7.35 (m, 2H) 7.45-7.59(m, 2H) 7.61-7.73 (m, 2H) 8.20 (s, 1H) 12.37 (s, 1H)

Example 2774-[cis-4-(4-acetylphenoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.88 g), sodium hydrogencarbonate (1.4 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C.for 30 min,4′-({4-[cis-4-(4-acetylphenoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.50 g) was added, and the mixture was stirred at 90° C. for 40 hr.Ethyl acetate and water were added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (4 mL). N,N′-Carbonyldiimidazole (0.16 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 mL) were added, andthe mixture was stirred at room temperature for 50 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was acidifiedwith 1 M hydrochloric acid and extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was heated under reflux in ethanol (10 mL)-20% sulfuricacid (5 mL) for 16 hr. The solvent was evaporated under reducedpressure, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure andthe residue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.097 g, 17%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.38 Hz, 3H) 1.46-1.62 (m, 4H)1.66-1.85 (m, 2H) 2.01-2.18 (m, 2H) 2.46-2.56 (m, 3H) 2.78-3.01 (m, 4H)3.97 (s, 2H) 4.72-4.88 (m, 1H) 4.93-5.12 (m, 1H) 7.12 (d, J=8.71 Hz, 2H)7.19-7.25 (m, 2H) 7.27-7.36 (m, 2H) 7.46-7.58 (m, 2H) 7.60-7.73 (m, 2H)7.94 (d, J=8.71 Hz, 2H) 8.23 (s, 1H) 12.37 (s, 1H)

Example 2784-[trans-4-(4-acetylphenoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.17 g), sodium hydrogencarbonate (0.28 g) and dimethyl sulfoxide (2 mL) was stirred at 40° C.for 30 min,4′-({4-[trans-4-(4-acetylphenoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.10 g) was added, and the mixture was stirred at 90° C. for 18 hr.Ethyl acetate and water were added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (1 mL). N,N′-Carbonyldiimidazole (0.034 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.032 mL) were added, andthe mixture was stirred at room temperature for 1 hr.N,N′-Carbonyldiimidazole (0.034 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.032 mL) were added, and themixture was stirred at room temperature for 18 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was acidifiedwith 1 M hydrochloric acid and extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was heated under reflux in ethanol (4 mL)-20% sulfuricacid (2 mL) for 5 hr. The solvent was evaporated under reduced pressure,and the mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography and recrystallized (ethylacetate-hexane) to give the title compound as a colorless solid (0.027g, 24%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.38 Hz, 3H) 1.47-1.66 (m, 4H)1.70-1.85 (m, 2H) 2.15-2.32 (m, 2H) 2.44-2.54 (m, 3H) 2.67-2.85 (m, 2H)2.89-3.01 (m, 2H) 3.97 (s, 2H) 4.45-4.62 (m, 1H) 4.90-5.08 (m, 1H) 7.10(d, J=8.71 Hz, 2H) 7.19-7.26 (m, 2H) 7.28-7.35 (m, 2H) 7.46-7.58 (m, 2H)7.62-7.72 (m, 2H) 7.90 (d, J=8.71 Hz, 2H) 8.21 (s, 1H) 12.39 (s, 1H)

Example 2794-{cis-4-[4-(1-hydroxy-1-methylethyl)phenoxy]cyclohexyl}-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.36 g), sodium hydrogencarbonate (0.58 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C.for 30 min,4′-[(4-{cis-4-[4-(1-hydroxy-1-methylethyl)phenoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.21 g) was added, and the mixture was stirred at 90° C. for 16 hr.Ethyl acetate and water were added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (1 mL). N,N′-Carbonyldiimidazole (0.060 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.055 mL) were added, andthe mixture was stirred at room temperature for 1.5 hr. Ethyl acetateand water were added to the reaction mixture, and the mixture wasacidified with 1 M hydrochloric acid and extracted with ethyl acetate.The organic layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.10 g,46%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.19 Hz, 3H) 1.40 (s, 6 H)1.45-1.82 (m, 6H) 1.99-2.15 (m, 2H) 2.80-3.05 (m, 4H) 3.97 (s, 2H)4.54-4.65 (m, 1H) 4.88 (s, 1H) 4.93-5.09 (m, 1H) 6.94 (d, J=8.71 Hz, 2H)7.19-7.26 (m, 2H) 7.28-7.42 (m, 4H) 7.47-7.58 (m, 2H) 7.62-7.73 (m, 2H)8.23 (s, 1H) 12.38 (br. s., 1H)

Example 2804-{trans-4-[4-(1-hydroxy-1-methylethyl)phenoxy]cyclohexyl}-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.29 g), sodium hydrogencarbonate (0.47 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C.for 30 min,4′-[(4-{trans-4-[4-(1-hydroxy-1-methylethyl)phenoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.17 g) was added, and the mixture was stirred at 90° C. for 16 hr.Hydroxylammonium chloride (0.097 g) and sodium hydrogen carbonate (0.15g) were further added, and the mixture was stirred at 90° C. for 4 hr.Ethyl acetate and water were added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (1 mL). N,N′-Carbonyldiimidazole (0.050 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.046 mL) were added, andthe mixture was stirred at room temperature for 2 hr.N,N′-Carbonyldiimidazole (0.050 g) and1,8-diazabicyclo[5.4.0]undec-7-ene (0.046 mL) were further added, andthe mixture was stirred at room temperature for 16 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was acidifiedwith 1 M hydrochloric acid and extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography andrecrystallized (ethyl acetate-hexane) to give the title compound as acolorless solid (0.087 g, 47%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.35 Hz, 3H) 1.39 (s, 6H)1.44-1.61 (m, 4H) 1.68-1.82 (m, 2H) 2.13-2.29 (m, 2H) 2.61-2.81 (m, 2H)2.86-3.01 (m, 2H) 3.97 (s, 2H) 4.16-4.41 (m, 1H) 4.87 (s, 1H) 4.90-5.09(m, 1H) 6.72-6.97 (m, 2H) 7.11-7.27 (m, 2H) 7.27-7.40 (m, 4H) 7.45-7.60(m, 2H) 7.60-7.74 (m, 2H) 8.21 (s, 1H) 12.38 (s, 1H)

Example 2814-[cis-4-(isoxazol-3-yloxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

4′-{[4-(trans-4-Hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.20 g), isoxazol-3-ol (0.071 g) and triphenylphosphine (0.22 g) weredissolved in tetrahydrofuran (2 mL), a solution of diisopropylazodicarboxylate (0.44 mL, 1.9 M toluene solution) in tetrahydrofuran (1mL) was added dropwise, and the mixture was stirred at room temperaturefor 18 hr. The reaction mixture was added to 1 M hydrochloric acid, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue obtainedby purification by silica gel column chromatography was added to amixture of hydroxylammonium chloride (0.43 g), sodium hydrogen carbonate(0.7 g), and dimethyl sulfoxide (3 mL), which had been stirred at 40° C.for 30 min in advance, and the mixture was stirred at 90° C. for 18 hr.Ethyl acetate and water were added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (1 mL). N,N′-Carbonyldiimidazole (0.081 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.074 mL) were added, andthe mixture was stirred at room temperature for 66 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was acidifiedwith 1 M hydrochloric acid and extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography andrecrystallized (ethyl acetate) to give the title compound as a colorlesssolid (0.055 g, 22%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.35 Hz, 3H) 1.44-1.86 (m, 6H)2.10-2.29 (m, 2H) 2.70-3.01 (m, 4H) 3.97 (s, 2H) 4.76-4.84 (m, 1H)4.93-5.09 (m, 1H) 6.41 (d, J=1.70 Hz, 1H) 7.19-7.26 (m, 2H) 7.28-7.35(m, 2H) 7.46-7.59 (m, 2H) 7.61-7.73 (m, 2H) 8.20 (s, 1H) 8.67 (d, J=1.88Hz, 1H) 12.38 (s, 1H)

Example 2824-[trans-4-(isoxazol-3-yloxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

4′-{[4-(cis-4-Hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.50 g), isoxazol-3-ol (0.18 g) and triphenylphosphine (0.55 g) weredissolved in tetrahydrofuran (2 mL), a solution of diisopropylazodicarboxylate (1.1 mL, 1.9 M toluene solution) in tetrahydrofuran (1mL) was added dropwise, and the mixture was stirred at room temperaturefor 96 hr. The reaction mixture was added to 1 M hydrochloric acid, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue obtainedby purification by silica gel column chromatography was added to amixture of hydroxylammonium chloride (1.1 g), sodium hydrogen carbonate(1.7 g), and dimethyl sulfoxide (3.5 mL), which had been stirred at 40°C. for 30 min in advance, and the mixture was stirred at 90° C. for 16hr. Ethyl acetate and water were added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.20 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.19 mL) were added, andthe mixture was stirred at room temperature for 3 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was acidifiedwith 1 M hydrochloric acid and extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography andrecrystallized (acetone-hexane) to give the title compound as acolorless solid (0.11 g, 18%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.35 Hz, 3H) 1.47-1.70 (m, 4H)1.72-1.86 (m, 2H) 2.23-2.36 (m, 2H) 2.58-2.79 (m, 2H) 2.87-3.01 (m, 2H)3.97 (s, 2H) 4.47-4.64 (m, 1H) 4.90-5.09 (m, 1H) 6.36 (d, J=1.70 Hz, 1H)7.18-7.25 (m, 2H) 7.28-7.35 (m, 2H) 7.46-7.59 (m, 2H) 7.62-7.73 (m, 2H)8.20 (s, 1H) 8.66 (d, J=1.70 Hz, 1H) 12.38 (s, 1H)

Example 2836-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl-4-[trans-4-(tetrahydro-2H-pyran-4-ylamino)cyclohexyl][1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.47 g), sodium hydrogencarbonate (0.76 g) and dimethyl sulfoxide (2 mL) was stirred at 40° C.for 30 min,4′-({5-oxo-7-propyl-4-[trans-4-(tetrahydro-2H-pyran-4-ylamino)cyclohexyl]-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.25 g) was added, and the mixture was stirred at 90° C. for 16 hr.Ethyl acetate and water were added to the reaction mixture, and themixture was extracted with ethyl acetate/2-propanol (3/1). The organiclayer was dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure. The residue was dissolved intetrahydrofuran (1.5 mL). N,N′-Carbonyldiimidazole (0.081 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.075 mL) were added, and themixture was stirred at room temperature for 20 hr.N,N′-Carbonyldiimidazole (0.081 g) and1,8-diazabicyclo[5.4.0]undec-7-ene (0.075 mL) were further added, andthe mixture was stirred at room temperature for 5 hr.N,N′-Carbonyldiimidazole (0.081 g) and1,8-diazabicyclo[5.4.0]undec-7-ene (0.075 mL) were further added, andthe mixture was stirred at room temperature for 20 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was adjustedto pH 6 with 1 M hydrochloric acid. The precipitate was collected byfiltration and washed with methanol to give the title compound as acolorless solid (0.11 g, 41%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.25 Hz, 3H) 1.31-1.78 (m, 8H)1.78-1.97 (m, 4H) 2.59-3.12 (m, 5H) 3.19-3.52 (m, 5H) 3.67-4.00 (m, 4H)4.71-5.01 (m, 1H) 7.14-7.28 (m, 4H) 7.35-7.50 (m, 2H) 7.50-7.62 (m, 2H)8.20 (s, 1H)

Example 2844-{trans-4-[methyl(tetrahydro-2H-pyran-4-yl)amino]cyclohexyl}-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.24 g), sodium hydrogencarbonate (0.40 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C.for 30 min,4′-[(4-{trans-4-[methyl(tetrahydro-2H-pyran-4-yl)amino]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.13 g) was added, and the mixture was stirred at 90° C. for 16 hr.Hydroxylammonium chloride (0.24 g) and sodium hydrogen carbonate (0.40g) were added, and the mixture was further stirred at 90° C. for 6 hr.Ethyl acetate and water were added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.046 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.043 mL) were added, andthe mixture was stirred at room temperature for 20 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was adjustedto pH 7 with 1 M hydrochloric acid and extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.044 g, 29%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.38 Hz, 3H) 1.16-1.73 (m, 12H)2.04-2.34 (m, 5H) 2.57-3.14 (m, 6H) 3.81-4.02 (m, 4H) 4.78-5.08 (m, 1H)7.15-7.37 (m, 4H) 7.41-7.58 (m, 2H) 7.58-7.71 (m, 2H) 8.17 (s, 1H) 12.32(br. s., 1H)

Example 2854-(3-methylidene-1,5-dioxaspiro[5.5]undec-9-yl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4-(4-oxocyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.20 g), 2-methylidenepropane-1,3-diol (0.067 g),4-methylbenzenesulfonic acid (0.0072 g) and toluene (20 mL) was heatedunder reflux for 1.5 hr using a Dean-Stark trap. After evaporation ofthe solvent under reduced pressure, the residue was purified by silicagel column chromatography to give the title compound as a colorlesssolid (0.043 g, 19%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.38 Hz, 3H) 1.31-1.67 (m, 6H)2.23-2.40 (m, 2H) 2.61-2.85 (m, 2H) 2.86-3.00 (m, 2H) 3.96 (s, 2H) 4.29(s, 2H) 4.32 (s, 2H) 4.87 (s, 2H) 4.90-5.08 (m, 1H) 7.16-7.25 (m, 2H)7.26-7.36 (m, 2H) 7.44-7.59 (m, 2H) 7.61-7.75 (m, 2H) 8.20 (s, 1H) 12.37(br. s., 1H)

Example 2864-(1,5-dioxaspiro[5.5]undec-9-yl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4-(4-oxocyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.20 g), propane-1,3-diol (0.058 g), 4-methylbenzenesulfonic acid(0.0072 g) and toluene (20 mL) was heated under reflux for 3 hr using aDean-Stark trap. The reaction mixture was added to saturated aqueoussodium hydrogen carbonate solution, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.087 g,39%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.38 Hz, 3H) 1.11-1.70 (m, 8H)2.23-2.44 (m, 2H) 2.59-2.80 (m, 2H) 2.85-3.01 (m, 2H) 3.76-3.90 (m, 4H)3.95 (s, 2H) 4.80-5.05 (m, 1H) 7.17-7.26 (m, 2H) 7.27-7.37 (m, 2H)7.45-7.59 (m, 2H) 7.61-7.74 (m, 2H) 8.19 (s, 1H) 12.37 (s, 1H)

Example 2874-(3-hydroxy-1,5-dioxaspiro[5.5]undec-9-yl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.4 g), sodium hydrogencarbonate (2.3 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C.for 30 min,4′-{[4-(3-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dioxaspiro[5.5]undec-9-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.91 g) was added, and the mixture was stirred at 90° C. for 15 hr.Ethyl acetate and water were added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.27 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.24 mL) were added, andthe mixture was stirred at room temperature for 1.5 hr. Ethyl acetateand water were added to the reaction mixture, and the mixture wasacidified with 1 M hydrochloric acid and extracted with ethyl acetate.The organic layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was dissolved in tetrahydrofuran (10 mL).Tetrabutylammonium fluoride (3.4 mL, 1.0 M tetrahydrofuran solution) wasadded and the mixture was stirred at 70° C. for 3.5 hr. The reactionmixture was added to 1 M hydrochloric acid, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.426 g, 51%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.19 Hz, 3H) 1.21-1.69 (m, 6H)2.02-2.15 (m, 2H) 2.54-2.79 (m, 2H) 2.86-3.00 (m, 2H) 3.44-3.63 (m, 3H)3.74-3.91 (m, 2H) 3.95 (s, 2H) 4.62-5.03 (m, 2H) 7.19-7.25 (m, 2H)7.27-7.34 (m, 2H) 7.45-7.59 (m, 2H) 7.61-7.72 (m, 2H) 8.15-8.22 (m, 1H)12.37 (br. s., 1H)

Example 2884-[cis-4-(2-hydroxyethoxy)cyclohexyl]-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4′-({4-[cis-4-(2-hydroxyethoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.44 g), 2,6-lutidine (0.15 mL), tert-butyl(dimethyl)silyltrifluoromethanesulfonate (0.29 mL) and tetrahydrofuran (5 mL) wasstirred at room temperature for 1.5 hr. The reaction mixture was addedto 1 M hydrochloric acid, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, the obtained residue was added to a mixture ofhydroxylammonium chloride (0.87 g), sodium hydrogen carbonate (1.4 g),and dimethyl sulfoxide (8 mL), which had been stirred at 40° C. for 30min in advance, and the mixture was stirred at 90° C. for 24 hr. Ethylacetate and water were added to the reaction mixture, and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The residue obtained bypurification by silica gel column chromatography was dissolved intetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.059 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.055 mL) were added, and themixture was stirred at room temperature for 5 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was acidifiedwith 1 M hydrochloric acid and extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was dissolved in tetrahydrofuran (10 mL).Tetrabutylammonium fluoride (0.77 mL, 1.0 M tetrahydrofuran solution)was added, and the mixture was stirred at 70° C. for 16 hr. The reactionmixture was added to 1 M hydrochloric acid, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.051 g, 10%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.19 Hz, 3H) 1.33-1.63 (m, 6H)1.91-2.05 (m, 2H) 2.35 (s, 3H) 2.68-2.96 (m, 4H) 3.42 (t, J=5.30 Hz, 2H)3.50-3.62 (m, 3H) 3.93 (s, 2H) 4.43-4.51 (m, 1H) 4.77-4.97 (m, 1H)7.18-7.25 (m, 2H) 7.26-7.32 (m, 2H) 7.45-7.59 (m, 2H) 7.61-7.74 (m, 2H)12.36 (br. s., 1H)

Example 2894-[trans-4-(2-hydroxyethoxy)cyclohexyl]-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4′-({4-[trans-4-(2-hydroxyethoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.60 g), 2,6-lutidine (0.20 mL), tert-butyl(dimethyl)silyltrifluoromethanesulfonate (0.39 mL) and tetrahydrofuran (5 mL) wasstirred at room temperature for 1.5 hr. The reaction mixture was addedto 1 M hydrochloric acid, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, the obtained residue was added to a mixture ofhydroxylammonium chloride (1.1 g), sodium hydrogen carbonate (1.9 g),and dimethyl sulfoxide (8 mL), which had been stirred at 40° C. for 30min in advance, and the mixture was stirred at 90° C. for 15 hr. Ethylacetate and water were added to the reaction mixture, and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The residue obtained bypurification by silica gel column chromatography was dissolved intetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (0.091 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.083 mL) were added, and themixture was stirred at room temperature for 1 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was acidifiedwith 1 M hydrochloric acid and extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was dissolved in tetrahydrofuran (10 mL).Tetrabutylammonium fluoride (1.1 mL, 1.0 M tetrahydrofuran solution) wasadded, and the mixture was stirred at 70° C. for 16 hr. The reactionmixture was added to 1 M hydrochloric acid, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography and recrystallized (ethylacetate-hexane) to give the title compound as a colorless solid (0.11 g,17%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.19 Hz, 3H) 1.21-1.38 (m, 2H)1.43-1.60 (m, 2H) 1.62-1.77 (m, 2H) 2.04-2.19 (m, 2H) 2.35 (s, 3H)2.52-2.67 (m, 2H) 2.80-2.95 (m, 2H) 3.24-3.39 (m, 1H) 3.47 (s, 4H) 3.93(s, 2H) 4.55 (br. s., 1H) 4.76-4.97 (m, 1H) 7.17-7.25 (m, 2H) 7.25-7.32(m, 2H) 7.45-7.59 (m, 2H) 7.60-7.74 (m, 2H) 12.40 (br. s., 1H)

Example 2904-(2,2-dimethyl-3-oxo-1,4-dioxaspiro[4.5]dec-8-yl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

To a solution of 2-hydroxy-2-methylpropanoic acid (0.17 g) and pyridine(0.42 mL) in tetrahydrofuran (5 mL) were added trimethylsilylbromide(0.68 mL) and then N,N-dimethylaminopyridine (0.040 g), and the mixturewas stirred at room temperature for 5 hr. Hexane was added to thereaction mixture, and the precipitate was filtered. The filtrate wasconcentrated under reduced pressure and the obtained residue (0.25 g),trimethylsilyltrifluoromethanesulfonate (0.21 mL),4-(4-oxocyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.21 g) and dichloromethane (5 mL) were mixed under an argon atmosphereat −78° C., and the mixture was stirred at room temperature for 15 hr.Trimethylsilyltrifluoromethanesulfonate (0.21 mL) was added, and themixture was further stirred at room temperature for 3 hr. Ethyl acetateand water were added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.037 g, 15%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.19 Hz, 3H) 1.43 (s, 3H) 1.47(s, 3H) 1.50-1.62 (m, 2H) 1.65-1.80 (m, 2H) 1.85-2.10 (m, 4H) 2.70-3.02(m, 4H) 3.96 (s, 2H) 4.89-5.16 (m, 1H) 7.17-7.25 (m, 2H) 7.28-7.36 (m,2H) 7.46-7.59 (m, 2H) 7.61-7.72 (m, 2H) 8.21 (s, 0.5H) 8.22 (s, 0.5H)12.36 (br. s., 1H)

Example 2914-[trans-4-(2-hydroxyethoxy)-4-methylcyclohexyl]-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4′-({4-[trans-4-(2-hydroxyethoxy)-4-methylcyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.28 g), 2,6-lutidine (0.12 mL), tert-butyl(dimethyl)silyltrifluoromethanesulfonate (0.24 mL) and tetrahydrofuran (3 mL) wasstirred at room temperature for 1.5 hr. The reaction mixture was addedto 1 M hydrochloric acid, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, the obtained residue was added to a mixture ofhydroxylammonium chloride (0.55 g), sodium hydrogen carbonate (0.89 g),and dimethyl sulfoxide (10 mL), which had been stirred at 40° C. for 30min in advance, and the mixture was stirred at 90° C. for 15 hr. Ethylacetate and water were added to the reaction mixture, and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The residue obtained bypurification by silica gel column chromatography was dissolved intetrahydrofuran (1 mL). N,N′-Carbonyldiimidazole (0.024 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.022 mL) were added, and themixture was stirred at room temperature for 5 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was acidifiedwith 1 M hydrochloric acid and extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was dissolved in tetrahydrofuran (8 mL),tetrabutylammonium fluoride (0.32 mL, 1.0 M tetrahydrofuran solution)was added, and the mixture was stirred at 70° C. for 16 hr. The reactionmixture was added to 1 M hydrochloric acid, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.024 g, 13%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.38 Hz, 3H) 1.32 (s, 3H)1.42-1.67 (m, 6H) 1.69-1.85 (m, 2H) 2.36 (s, 3H) 2.55-2.78 (m, 2H)2.81-2.95 (m, 2H) 3.36-3.52 (m, 4H) 3.93 (s, 2H) 4.41-4.53 (m, 1H)4.76-4.98 (m, 1H) 7.18-7.25 (m, 2H) 7.26-7.33 (m, 2H) 7.45-7.59 (m, 2H)7.61-7.74 (m, 2H) 12.36 (br. s., 1H)

Example 2924-(1,4-dioxaspiro[4.5]dec-8-yl)-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.9 g), sodium hydrogencarbonate (3.2 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(1.0 g) was added, and the mixture was stirred at 90° C. for 16 hr.Ethyl acetate and water were added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.37 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.34 mL) were added, andthe mixture was stirred at room temperature 19 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was acidifiedwith 1 M hydrochloric acid and extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography andrecrystallized (ethyl acetate-hexane) to give the title compound as acolorless solid (0.83 g, 74%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.38 Hz, 3H) 1.44-1.86 (m, 8H)2.36 (s, 3H) 2.66-2.97 (m, 4H) 3.82-3.98 (m, 6 H) 4.78-5.05 (m, 1H)7.18-7.25 (m, 2H) 7.26-7.33 (m, 2H) 7.44-7.59 (m, 2H) 7.61-7.74 (m, 2H)12.36 (s, 1H)

Example 2936-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl-4-(tetrahydrospiro[cyclohexane-1,2′-furo[3,4-d][1,3]dioxol]-4-yl)[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4-(4-oxocyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.30 g), tetrahydrofuran-3,4-diol (0.11 g), 4-methylbenzenesulfonicacid (0.011 g) and toluene (20 mL) was heated under reflux for 6 hrusing a Dean-Stark trap. The reaction mixture was added to saturatedaqueous sodium hydrogen carbonate solution, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography and recrystallized (ethylacetate-hexane) to give the title compound as a colorless solid (0.23 g,68%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.19 Hz, 3H) 1.40-1.98 (m, 8H)2.67-3.00 (m, 4H) 3.32-3.41 (m, 2H) 3.87 (dd, J=25.75, 10.60 Hz, 2H)3.95 (s, 2H) 4.69-4.85 (m, 2H) 4.86-5.06 (m, 1H) 7.18-7.25 (m, 2H)7.27-7.33 (m, 2H) 7.44-7.58 (m, 2H) 7.61-7.74 (m, 2H) 8.20 (s, 1H) 12.37(s, 1H)

Example 2944-[2-(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-8-yl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4-(4-oxocyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.30 g), 1,2-dihydroxyethyl acetate (0.15 g), 4-methylbenzenesulfonicacid (0.011 g) and toluene (20 mL) was heated under reflux for 24 hrusing a Dean-Stark trap. The reaction mixture was added to saturatedaqueous sodium hydrogen carbonate solution, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was dissolved in1 M aqueous sodium hydroxide solution (3 mL), tetrahydrofuran (3 mL) andmethanol (3 mL), and the mixture was stirred at 50° C. for 15 hr. Thesolvent was evaporated under reduced pressure, the residue was adjustedto pH 7 with 1 M hydrochloric acid, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography and HPLC to give the title compound as a colorless solid(0.081 g, 23%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.19 Hz, 3H) 1.44-1.96 (m, 8H)2.62-3.03 (m, 4H) 3.38-3.77 (m, 3H) 3.95 (s, 2H) 3.97-4.18 (m, 2H)4.71-4.88 (m, 1H) 4.89-5.07 (m, 1H) 7.18-7.25 (m, 2H) 7.26-7.35 (m, 2H)7.44-7.59 (m, 2H) 7.59-7.78 (m, 2H) 8.18 (s, 0.5H) 8.19 (s, 0.5H) 12.37(br. s., 1H)

Example 2952-methyl-4-(4-oxocyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4-(1,4-dioxaspiro[4.5]dec-8-yl)-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.76 g), 6M hydrochloric acid (3 mL) and tetrahydrofuran (4 mL) wasstirred at 70° C. for 22 hr. The reaction mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography and recrystallized (ethyl acetate) to give the titlecompound as a colorless solid (0.31 g, 44%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.35 Hz, 3H) 1.43-1.62 (m, 2H)1.92-2.08 (m, 2H) 2.24-2.34 (m, 2H) 2.36 (s, 3H) 2.55-2.74 (m, 2H)2.76-2.98 (m, 4H) 3.95 (s, 2H) 5.30-5.54 (m, 1H) 7.18-7.25 (m, 2H)7.27-7.34 (m, 2H) 7.46-7.59 (m, 2H) 7.62-7.72 (m, 2H) 12.38 (s, 1H)

Example 2964-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.44 g), sodium hydrogencarbonate (0.72 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.23 g) was added, and the mixture was stirred at 90° C. for 21 hr.Ethyl acetate and water were added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.084 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.078 mL) were added, andthe mixture was stirred at room temperature for 18 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was acidifiedwith 1 M hydrochloric acid and extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.10 g, 39%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.25 Hz, 3H) 1.07 (s, 6H)1.19-1.38 (m, 2H) 1.43-1.59 (m, 2H) 1.60-1.75 (m, 2 H) 1.99-2.18 (m, 2H)2.35 (s, 3H) 2.42-2.66 (m, 2H) 2.81-2.93 (m, 2H) 3.20 (s, 2H) 3.25-3.37(m, 1H) 3.93 (s, 2H) 4.23 (s, 1H) 4.77-4.96 (m, 1H) 7.17-7.24 (m, 2H)7.26-7.34 (m, 2H) 7.45-7.59 (m, 2H) 7.61-7.72 (m, 2H) 12.37 (br. s., 1H)

Example 2974-[cis-4-hydroxy-4-(methoxymethyl)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.73 g), sodium hydrogencarbonate (1.1 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-({4-[cis-4-hydroxy-4-(methoxymethyl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.35 g) was added, and the mixture was stirred at 90° C. for 22 hr.Ethyl acetate and water were added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (0.13 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.12 mL) were added, andthe mixture was stirred at room temperature for 20 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was acidifiedwith 1 M hydrochloric acid and extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography andrecrystallized (ethyl acetate-hexane) to give the title compound as acolorless solid (0.15 g, 39%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.25 Hz, 3H) 1.34-1.67 (m, 8H)2.83-3.01 (m, 4H) 3.13 (s, 2H) 3.28 (s, 3H) 3.96 (s, 2H) 4.23 (s, 1H)4.75-4.92 (m, 1H) 7.17-7.26 (m, 2H) 7.28-7.34 (m, 2H) 7.47-7.59 (m, 2H)7.61-7.73 (m, 2 H) 8.18 (s, 1H) 12.38 (s, 1H)

Example 2984-[4-(2-hydroxy-2-methylpropoxy)phenyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.28 g), sodium hydrogencarbonate (0.45 g) and dimethyl sulfoxide (2 mL) was stirred at 40° C.for 30 min,4′-({4-[4-(2-hydroxy-2-methylpropoxy)phenyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.14 g) was added, and the mixture was stirred at 90° C. for 22 hr.Ethyl acetate and water were added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.054 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.049 mL) were added, andthe mixture was stirred at room temperature for 60 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was acidifiedwith 1 M hydrochloric acid and extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.052 g, 32%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.96 (t, J=7.25 Hz, 3H) 1.23 (s, 6H)1.49-1.70 (m, 2H) 2.89-3.07 (m, 2H) 3.78 (s, 2H) 4.00 (s, 2H) 4.68 (s,1H) 7.07 (d, J=8.85 Hz, 2H) 7.23 (d, J=8.10 Hz, 2H) 7.31-7.41 (m, 4H)7.46-7.60 (m, 2H) 7.62-7.73 (m, 2H) 8.06 (s, 1H) 12.39 (br. s., 1H)

Example 2994-[trans-4-(2-hydroxy-1-methylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(1.0 g), butane-2,3-diol (0.38 g), 4-methylbenzenesulfonic acid (0.042g) and toluene (20 mL) was heated under reflux for 9 hr using aDean-Stark trap. The reaction mixture was added to saturated aqueoussodium hydrogen carbonate solution, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was dissolved in tetrahydrofuran (20mL), sodium cyanoborohydride (0.67 g) and boron trifluoride etherate(1.3 mL) were added, and the mixture was heated under reflux for 7 hr.The reaction mixture was added to saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. 40% of the residue obtained by purification by silica gelcolumn chromatography was mixed with 2,6-lutidine (0.20 mL),tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.40 mL) andtetrahydrofuran (2 mL), and the mixture was stirred at room temperature7 hr. The reaction mixture was added to 1 M hydrochloric acid, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated aqueous sodium hydrogen carbonate solution and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, the obtained residue was added toa mixture of hydroxylammonium chloride (0.45 g), sodium hydrogencarbonate (0.73 g), and dimethyl sulfoxide (3 mL), which had beenstirred at 40° C. for 30 min in advance, and the mixture was stirred at90° C. for 40 hr. Ethyl acetate and water were added to the reactionmixture, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The residue obtained by purification by silica gel column chromatographywas dissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.060g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.055 mL) were added,and the mixture was stirred at room temperature for 2 hr. Ethyl acetateand water were added to the reaction mixture, and the mixture wasacidified with 1 M hydrochloric acid and extracted with ethyl acetate.The organic layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was dissolved in tetrahydrofuran (2 mL),tetrabutylammonium fluoride (0.75 mL, 1.0 M tetrahydrofuran solution)was added, and the mixture was heated under reflux for 2 hr. Thereaction mixture was added to 1 M hydrochloric acid, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography and recrystallized (ethylacetate-hexane) to give the title compound as a colorless solid (0.067g, 13%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.35 Hz, 3H) 0.96-1.02 (m, 2.4H)1.05 (d, J=6.22 Hz, 3.6H) 1.21-1.39 (m, 2H) 1.43-1.62 (m, 2H) 1.62-1.77(m, 2H) 2.00-2.14 (m, 2H) 2.41-2.69 (m, 2H) 2.86-2.99 (m, 2H) 3.22-3.62(m, 3H) 3.95 (s, 2H) 4.33 (d, J=4.52 Hz, 0.4H) 4.41 (d, J=5.09 Hz, 0.6H)4.78-5.03 (m, 1H) 7.17-7.25 (m, 2H) 7.27-7.34 (m, 2H) 7.45-7.59 (m, 2H)7.61-7.74 (m, 2H) 8.18 (s, 1H) 12.38 (s, 1H)

Example 3004-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.36 g), sodium hydrogencarbonate (0.58 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C.for 30 min,4′-({4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.19 g) was added, and the mixture was stirred at 90° C. for 15 hr.Ethyl acetate and water were added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.070 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.065 mL) were added, andthe mixture was stirred at room temperature for 1 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was acidifiedwith 1 M hydrochloric acid and extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.12 g, 58%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.35 Hz, 3H) 1.00 (s, 3H) 1.04(d, J=6.22 Hz, 3H) 1.08 (s, 3H) 1.22-1.41 (m, 2H) 1.44-1.61 (m, 2H)1.62-1.76 (m, 2H) 1.94-2.19 (m, 2H) 2.52-2.69 (m, 2H) 2.85-3.00 (m, 2H)3.25 (q, J=6.22 Hz, 1H) 3.34-3.47 (m, 1H) 3.96 (s, 2H) 4.06 (s, 1H)4.78-5.02 (m, 1H) 7.18-7.26 (m, 2H) 7.27-7.36 (m, 2H) 7.46-7.59 (m, 2H)7.61-7.75 (m, 2H) 8.18 (s, 1H) 12.38 (br. s., 1H)

Example 3014-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-2-methyl-7-propyl-6-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4′-({4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.24 g), trimethylsilylazide (1.4 g), dibutyltinoxide (0.052 g) andtoluene (15 mL) was heated under reflux for 134 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated brine,and dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure, and the residue was dissolved in tetrahydrofuran(10 mL). Tetrabutylammonium fluoride (1.0 mL, 1.0 M tetrahydrofuransolution) was added, and the mixture was stirred at 70° C. for 4 hr. Thereaction mixture was added to 1 M hydrochloric acid, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography and recrystallized (ethyl acetate) togive the title compound as a colorless solid (0.070 g, 26%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (t, J=7.25 Hz, 3H) 1.00 (s, 3H) 1.03(d, J=6.22 Hz, 3H) 1.08 (s, 3H) 1.20-1.77 (m, 6H) 2.00-2.18 (m, 2H) 2.35(s, 3H) 2.53-2.66 (m, 2H) 2.76-2.91 (m, 2H) 3.19-3.29 (m, 1H) 3.35-3.45(m, 1H) 3.87 (s, 2H) 4.06 (s, 1H) 4.65-4.96 (m, 1H) 6.78-8.04 (m, 9H)

Example 3024-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.26 g), sodium hydrogencarbonate (0.42 g) and dimethyl sulfoxide (2 mL) was stirred at 40° C.for 1.5 hr,4′-({4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.14 g) was added, and the mixture was stirred at 90° C. for 14 hr.Ethyl acetate and water were added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.044 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.041 mL) were added, andthe mixture was stirred at room temperature for 4 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was acidifiedwith 1 M hydrochloric acid and extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.078 g, 50%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.25 Hz, 3H) 1.00 (s, 3H) 1.03(d, J=6.22 Hz, 3H) 1.08 (s, 3H) 1.21-1.42 (m, 2H) 1.45-1.59 (m, 2H)1.61-1.75 (m, 2H) 1.95-2.17 (m, 2H) 2.35 (s, 3H) 2.43-2.69 (m, 2H)2.81-2.96 (m, 2H) 3.26 (q, J=6.22 Hz, 1H) 3.33-3.47 (m, 1H) 3.93 (s, 2H)4.06 (s, 1H) 4.73-4.96 (m, 1H) 7.16-7.25 (m, 2H) 7.26-7.33 (m, 2H)7.44-7.59 (m, 2H) 7.61-7.73 (m, 2H) 12.37 (s, 1H)

Example 3034-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

To a solution of4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.047 g) in tetrahydrofuran (2 mL) was added 0.1 M aqueous potassiumhydroxide solution (0.77 mL), and the solvent was evaporated underreduced pressure. The residue was washed with diisopropyl ether to givethe title compound as a colorless solid (0.036 g, 71%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.25 Hz, 3H) 1.07 (s, 6H)1.18-1.38 (m, 2H) 1.49-1.75 (m, 4H) 2.01-2.17 (m, 2H) 2.35 (s, 3H)2.42-2.67 (m, 2H) 2.81-2.97 (m, 2H) 3.20 (s, 2H) 3.24-3.37 (m, 1H) 3.88(s, 2H) 4.23 (s, 1H) 4.77-4.96 (m, 1H) 7.11-7.18 (m, 2H) 7.18-7.23 (m,2H) 7.24-7.50 (m, 4H)

Example 3044-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

To a solution of4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.095 g) in tetrahydrofuran (2 mL) was added 0.1 M aqueous potassiumhydroxide solution (1.5 mL), and the solvent was evaporated underreduced pressure. The residue was washed with diisopropyl ether to givethe title compound as a colorless solid (0.086 g, 85%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.96 (t, J=7.35 Hz, 3H) 0.99 (s, 3H) 1.04(d, J=6.03 Hz, 3H) 1.08 (s, 3H) 1.19-1.42 (m, 2H) 1.49-1.77 (m, 4H)1.92-2.17 (m, 2H) 2.52-2.68 (m, 2H) 2.85-3.02 (m, 2H) 3.24 (q, J=6.22Hz, 1H) 3.33-3.46 (m, 1H) 3.90 (s, 2H) 4.06 (s, 1H) 4.75-5.01 (m, 1H)7.13-7.51 (m, 8H) 8.16 (s, 1H)

Example 3054-[trans-4-(2-hydroxy-1-methylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

To a solution of4-[trans-4-(2-hydroxy-1-methylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.039 g) in tetrahydrofuran (2 mL) was added 0.1 M aqueous potassiumhydroxide solution (0.65 mL), and the solvent was evaporated underreduced pressure. The residue was washed with diisopropyl ether to givethe title compound as a colorless solid (0.025 g, 61%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89-1.09 (m, 9H) 1.20-1.38 (m, 2H)1.50-1.76 (m, 4H) 1.94-2.14 (m, 2H) 2.41-2.69 (m, 2H) 2.88-3.02 (m, 2H)3.21-3.58 (m, 3H) 3.90 (s, 2H) 4.33 (d, J=4.52 Hz, 0.5H) 4.41 (d, J=5.09Hz, 0.5H) 4.80-5.00 (m, 1H) 7.12-7.51 (m, 8H) 8.16 (s, 1H)

Example 3064-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

To a solution of4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.057 g) in tetrahydrofuran (2 mL) was added 0.1 M aqueous potassiumhydroxide solution (0.91 mL), and the solvent was evaporated underreduced pressure. The residue was washed with diisopropyl ether to givethe title compound as a colorless solid (0.031 g, 52%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.38 Hz, 3H) 0.99 (s, 3H) 1.03(d, J=6.06 Hz, 3H) 1.08 (s, 3H) 1.17-1.37 (m, 2H) 1.46-1.60 (m, 2H)1.61-1.74 (m, 2H) 1.93-2.15 (m, 2H) 2.35 (s, 3H) 2.46-2.67 (m, 2H)2.82-2.96 (m, 2H) 3.26 (q, J=6.06 Hz, 1H) 3.34-3.43 (m, 1H) 3.91 (s, 2H)4.06 (s, 1H) 4.75-4.96 (m, 1H) 7.15-7.28 (m, 4H) 7.37-7.52 (m, 2H)7.52-7.64 (m, 2H)

Example 3074-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-7-propyl-6-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4′-({4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.33 g), trimethylsilylazide (1.9 g), dibutyltinoxide (0.14 g) andtoluene (15 mL) was stirred at 110° C. for 88 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated brine,and dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure, and the residue was dissolved in tetrahydrofuran(10 mL). Tetrabutylammonium fluoride (2.3 mL, 1.0 M tetrahydrofuransolution) was added, and the mixture was stirred at 70° C. for 1 hr. Thereaction mixture was added to 1 M hydrochloric acid, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography and recrystallized (ethylacetate-diisopropyl ether) to give the title compound as a colorlesssolid (0.10 g, 30%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91 (t, J=7.25 Hz, 3H) 0.99 (s, 3H) 1.03(d, J=6.03 Hz, 3H) 1.08 (s, 3H) 1.21-1.77 (m, 6H) 1.94-2.17 (m, 2H)2.53-2.68 (m, 2H) 2.83-2.98 (m, 2H) 3.18-3.29 (m, 1H) 3.35-3.45 (m, 1H)3.90 (s, 2H) 4.06 (s, 1H) 4.78-4.98 (m, 1H) 6.77-7.78 (m, 9H) 8.17 (s,1H)

Example 3084-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)-4-methylcyclohexyl]-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.30 g), sodium hydrogencarbonate (0.48 g) and dimethyl sulfoxide (2 mL) was stirred at 40° C.for 30 min,4′-({4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)-4-methylcyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.17 g) was added, and the mixture was stirred at 90° C. for 15 hr.Ethyl acetate and water were added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.057 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.052 mL) were added, andthe mixture was stirred at room temperature for 1.5 hr. Ethyl acetateand water were added to the reaction mixture, and the mixture wasacidified with 1 M hydrochloric acid and extracted with ethyl acetate.The organic layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography and HPLC to give the title compound as a colorless solid(0.11 g, 68%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91 (t, J=7.19 Hz, 3H) 0.99 (s, 3H) 1.06(d, J=6.06 Hz, 3H) 1.08 (s, 3H) 1.33 (s, 3H) 1.38-1.83 (m, 8H) 2.35 (s,3H) 2.55-2.98 (m, 4H) 3.48 (q, J=5.68 Hz, 1H) 3.93 (s, 2H) 4.11-6.19 (m,2H) 7.16-7.36 (m, 4H) 7.46-7.60 (m, 2H) 7.62-7.74 (m, 2H) 12.37 (s, 1H)

Example 3094-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-2-methyl-7-propyl-6-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

To a solution of4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-2-methyl-7-propyl-6-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.041 g) in tetrahydrofuran (2 mL) was added 0.1 M aqueous potassiumhydroxide solution (0.67 mL), and the solvent was evaporated underreduced pressure. The residue was washed with diisopropyl ether to givethe title compound as a colorless solid (0.035 g, 80%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.25 Hz, 3H) 0.99 (s, 3H) 1.03(d, J=6.22 Hz, 3H) 1.08 (s, 3H) 1.15-1.37 (m, 2H) 1.47-1.74 (m, 4H)1.92-2.17 (m, 2H) 2.35 (s, 3H) 2.45-2.66 (m, 2H) 2.80-2.93 (m, 2H)3.20-3.29 (m, 1H) 3.35-3.43 (m, 1H) 3.83 (s, 2H) 4.06 (s, 1H) 4.72-4.96(m, 1H) 6.95-7.10 (m, 4H) 7.23-7.42 (m, 3H) 7.45-7.55 (m, 1H)

Example 3104-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)-4-methylcyclohexyl]-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

To a solution of4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)-4-methylcyclohexyl]-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.044 g) in tetrahydrofuran (2 mL) was added 0.1 M aqueous potassiumhydroxide solution (0.69 mL), and the solvent was evaporated underreduced pressure. The residue was washed with diisopropyl ether to givethe title compound as a colorless solid (0.034 g, 71%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.35 Hz, 3H) 0.99 (s, 3H) 1.06(d, J=6.22 Hz, 3H) 1.08 (s, 3H) 1.33 (s, 3H) 1.42-1.85 (m, 8H) 2.35 (s,3H) 2.54-2.81 (m, 2H) 2.82-2.99 (m, 2H) 3.48 (q, J=6.03 Hz, 1H) 3.88 (s,2H) 3.94 (s, 1H) 4.76-5.00 (m, 1H) 7.09-7.53 (m, 8H)

Example 3114-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-7-propyl-6-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

To a solution of4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-7-propyl-6-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.068 g) in tetrahydrofuran (2 mL) was added 0.1 M aqueous potassiumhydroxide solution (1.1 mL), and the solvent was evaporated underreduced pressure. The residue was washed with diisopropyl ether to givethe title compound as a colorless solid (0.062 g, 85%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.19 Hz, 3H) 0.99 (s, 3H) 1.03(d, J=6.06 Hz, 3H) 1.08 (s, 3H) 1.13-1.40 (m, 2H) 1.49-1.80 (m, 4H)1.92-2.17 (m, 2H) 2.40-2.69 (m, 2H) 2.85-2.98 (m, 2H) 3.24 (q, J=6.06Hz, 1H) 3.29-3.43 (m, 1H) 3.86 (s, 2H) 4.06 (s, 1H) 4.76-4.98 (m, 1H)6.98-7.03 (m, 2H) 7.04-7.10 (m, 2H) 7.24-7.41 (m, 3H) 7.44-7.54 (m, 1H)8.16 (s, 1H)

Example 3124-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)-4-methylcyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.91 g), sodium hydrogencarbonate (1.4 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-({4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)-4-methylcyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.50 g) was added, and the mixture was stirred at 90° C. for 16 hr.Ethyl acetate and water were added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.17 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 mL) were added, andthe mixture was stirred at room temperature for 1.5 hr. Ethyl acetateand water were added to the reaction mixture, and the mixture wasacidified with 1 M hydrochloric acid and extracted with ethyl acetate.The organic layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography and recrystallized (ethyl acetate) to give the titlecompound as a colorless solid (0.26 g, 47%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.35 Hz, 3H) 0.99 (s, 3H)1.03-1.10 (m, 6H) 1.34 (s, 3H) 1.45-1.85 (m, 8H) 2.56-2.77 (m, 2H)2.87-3.00 (m, 2H) 3.48 (q, J=6.03 Hz, 1H) 3.94 (s, 1H) 3.96 (s, 2H)4.80-5.07 (m, 1H) 7.17-7.26 (m, 2H) 7.27-7.36 (m, 2H) 7.47-7.59 (m, 2H)7.61-7.75 (m, 2H) 8.21 (s, 1H) 12.38 (br. s., 1H)

Example 3134-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)-4-methylcyclohexyl]-7-propyl-6-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4′-({4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)-4-methylcyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.50 g), trimethylsilylazide (3.0 g), dibutyltinoxide (0.10 g) andtoluene (10 mL) was stirred at 110° C. for 40 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated brine,and dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure, and the residue was dissolved in tetrahydrofuran(10 mL). Tetrabutylammonium fluoride (3.5 mL, 1.0 M tetrahydrofuransolution) was added, and the mixture was heated under reflux for 1.5 hr.The reaction mixture was added to 1 M hydrochloric acid, and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography and recrystallized (ethylacetate-diisopropyl ether) to give the title compound as a colorlesssolid (0.30 g, 56%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91 (t, J=7.25 Hz, 3H) 0.99 (s, 3H)1.03-1.10 (m, 6H) 1.34 (s, 3H) 1.43-1.84 (m, 8H) 2.54-2.76 (m, 2H)2.82-2.95 (m, 2H) 3.48 (q, J=6.15 Hz, 1H) 3.90 (s, 2H) 3.94 (s, 1H)4.82-5.01 (m, 1H) 6.59-7.83 (m, 9H) 8.20 (s, 1H)

Example 3144-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)-4-methylcyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

To a solution of4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)-4-methylcyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.12 g) in tetrahydrofuran (5 mL) was added 0.1 M aqueous potassiumhydroxide solution (2.0 mL), and the solvent was evaporated underreduced pressure. The residue was washed with diisopropyl ether to givethe title compound as a colorless solid (0.11 g, 80%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.35 Hz, 3H) 0.99 (s, 3H) 1.06(d, J=6.22 Hz, 3H) 1.08 (s, 3H) 1.34 (s, 3H) 1.48-1.85 (m, 8H) 2.56-2.76(m, 2H) 2.89-3.01 (m, 2H) 3.48 (q, J=6.03 Hz, 1H) 3.92 (s, 2H) 3.94 (s,1H) 4.82-5.02 (m, 1H) 7.15-7.26 (m, 4H) 7.28-7.41 (m, 2H) 7.42-7.53 (m,2H) 8.19 (s, 1H)

Example 3154-[4-hydroxy-4-(tetrahydro-2H-pyran-4-yl)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.24 g), sodium hydrogencarbonate (0.38 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C.for 30 min,4′-({4-[4-hydroxy-4-(tetrahydro-2H-pyran-4-yl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.12 g) was added, and the mixture was stirred at 90° C. for 24 hr.Ethyl acetate and water were added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.045 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.042 mL) were added, andthe mixture was stirred at room temperature for 3 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was acidifiedwith 1 M hydrochloric acid and extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.020 g, 14%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.25 Hz, 3H) 1.26-1.47 (m, 7H)1.48-1.72 (m, 6H) 2.83-3.04 (m, 4H) 3.16-3.40 (m, 2H) 3.83-3.99 (m, 5H)4.74-4.95 (m, 1H) 7.18-7.26 (m, 2H) 7.27-7.34 (m, 2H) 7.46-7.59 (m, 2H)7.61-7.73 (m, 2H) 8.18 (s, 1H) 12.38 (br. s., 1H)

Example 3166-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl-4-[trans-4-(4H-1,2,4-triazol-3-ylmethoxy)cyclohexyl][1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of tert-butyl2-{[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetyl}hydrazinecarboxylate(0.69 g), trifluoroacetic acid (1 mL) and toluene (7 mL) was stirred atroom temperature for 1 hr. Trifluoroacetic acid (5 mL) was furtheradded, and the mixture was stirred at 50° C. for 2 hr. 1 M Aqueoussodium hydroxide solution was added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue was mixedwith ethyl imidoformate hydrochloride (0.18 g), triethylamine (5 mL) andethanol (20 mL), and the mixture was heated under reflux for 118 hr. Thesolvent was evaporated under reduced pressure, the residue obtained bysilica gel column chromatography was added to a mixture ofhydroxylammonium chloride (0.18 g), sodium hydrogen carbonate (0.30 g),and dimethyl sulfoxide (1 mL), which had been stirred at 40° C. for 30min in advance, and the mixture was stirred at 90° C. for 24 hr. Ethylacetate and water were added to the reaction mixture, and the mixturewas extracted with ethyl acetate/2-propanol (3/1). The organic layer wasdried over anhydrous sodium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was dissolved in tetrahydrofuran (1mL). N,N′-Carbonyldiimidazole (0.029 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.027 mL) were added, and themixture was stirred at room temperature for 1 hr.N,N′-Carbonyldiimidazole (0.058 g) and1,8-diazabicyclo[5.4.0]undec-7-ene (0.054 mL) were added, and themixture was stirred at room temperature for 15 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was adjustedto pH 3 with 1 M hydrochloric acid. The mixture was extracted with ethylacetate, and the organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography and HPLC to give the title compound as a colorless solid(0.020 g, 6%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.35 Hz, 3H) 1.19-1.42 (m, 2H)1.46-1.62 (m, 2H) 1.64-1.83 (m, 2H) 2.09-2.21 (m, 2H) 2.53-2.69 (m, 2H)2.83-3.04 (m, 2H) 3.34-3.59 (m, 1H) 3.96 (s, 2H) 4.61 (s, 2H) 4.76-5.05(m, 1H) 5.10-6.87 (m, 1H) 7.17-7.27 (m, 2H) 7.27-7.37 (m, 2H) 7.45-7.61(m, 2H) 7.61-7.75 (m, 2H) 8.17 (s, 1H) 8.33 (s, 1H) 12.38 (s, 1H)

Example 3176-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-{trans-4-[(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)methoxy]cyclohexyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.33 g), sodium hydrogencarbonate (0.53 g) and dimethyl sulfoxide (2 mL) was stirred at 40° C.for 30 min,4′-({4-[trans-4-(1,3,4-oxadiazol-2-ylmethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.17 g) was added, and the mixture was stirred at 90° C. for 11 hr.Ethyl acetate and water were added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.064 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.059 mL) were added, andthe mixture was stirred at room temperature for 1 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was acidifiedwith 1 M hydrochloric acid and extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.025 g, 12%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.25 Hz, 3H) 1.22-1.43 (m, 2H)1.45-1.62 (m, 2H) 1.65-1.79 (m, 2H) 2.06-2.19 (m, 2H) 2.47-2.68 (m, 2H)2.86-3.01 (m, 2H) 3.38-3.59 (m, 1H) 3.95 (s, 2H) 4.42 (s, 2H) 4.81-5.01(m, 1H) 7.18-7.25 (m, 2H) 7.28-7.34 (m, 2H) 7.46-7.59 (m, 2H) 7.61-7.73(m, 2H) 8.18 (s, 1H) 12.37 (br. s., 2H)

Example 3184-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(retention time: short)

A mixture of hydroxylammonium chloride (0.16 g), sodium hydrogencarbonate (0.26 g) and dimethyl sulfoxide (1.5 mL) was stirred at 40° C.for 30 min,4′-({4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(retention time: short, 0.088 g) obtained in Reference Example 308 wasadded, and the mixture was stirred at 90° C. for 10 hr. Ethyl acetateand water were added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was dissolved intetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.031 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.028 mL) were added, and themixture was stirred at room temperature for 2 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was acidifiedwith 1 M hydrochloric acid and extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.046 g, >99% ee, 47%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.35 Hz, 3H) 0.99 (s, 3H) 1.03(d, J=6.22 Hz, 3H) 1.08 (s, 3H) 1.21-1.39 (m, 2H) 1.44-1.61 (m, 2H)1.62-1.77 (m, 2H) 1.96-2.17 (m, 2H) 2.46-2.69 (m, 2H) 2.85-3.02 (m, 2H)3.25 (q, J=6.40 Hz, 1H) 3.34-3.46 (m, 1H) 3.95 (s, 2H) 4.06 (s, 1H)4.75-5.01 (m, 1H) 7.17-7.26 (m, 2H) 7.27-7.34 (m, 2H) 7.45-7.59 (m, 2H)7.61-7.72 (m, 2H) 8.18 (s, 1H) 12.38 (s, 1H)

Enantiomeric Excess Measurement Condition

CHIRALPACK AD-H 4.6 mm ID×150 mL LI-015

CO₂/2-Propanol=700/300

5.00 ml/min

retention time 1.82 min

Example 3194-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(retention time: long)

A mixture of hydroxylammonium chloride (0.13 g), sodium hydrogencarbonate (0.21 g) and dimethyl sulfoxide (1.5 mL) was stirred at 40° C.for 30 min,4′-({4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(retention time: long, 0.071 g) obtained in Reference Example 309 wasadded, and the mixture was stirred at 90° C. for 10 hr. Ethyl acetateand water were added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was dissolved intetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.025 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.023 mL) were added, and themixture was stirred at room temperature for 2 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was acidifiedwith 1 M hydrochloric acid and extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.046 g, >99% ee, 59%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.35 Hz, 3H) 0.99 (s, 3H) 1.03(d, J=6.40 Hz, 3H) 1.08 (s, 3H) 1.20-1.41 (m, 2H) 1.48-1.62 (m, 2H)1.63-1.75 (m, 2H) 1.93-2.15 (m, 2H) 2.44-2.69 (m, 2H) 2.88-3.00 (m, 2H)3.25 (q, J=6.15 Hz, 1H) 3.33-3.46 (m, 1H) 3.95 (s, 2H) 4.06 (s, 1H)4.81-4.99 (m, 1H) 7.18-7.26 (m, 2H) 7.27-7.35 (m, 2H) 7.45-7.59 (m, 2H)7.62-7.73 (m, 2H) 8.18 (s, 1H) 12.38 (s, 1H)

Enantiomeric Excess Measurement Condition

CHIRALPACK AD-H 4.6 mm ID×150 mL LI-015

CO₂/2-Propanol=700/300

5.00 ml/min

retention time 2.55 min

Example 3204-[1-(2-hydroxy-2-methylpropyl)-4,5,6,7-tetrahydro-1H-indazol-5-yl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.12 g), sodium hydrogencarbonate (0.20 g) and dimethyl sulfoxide (2 mL) was stirred at 40° C.for 30 min,4′-({4-[1-(2-hydroxy-2-methylpropyl)-4,5,6,7-tetrahydro-1H-indazol-5-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.069 g) was added, and the mixture was stirred at 90° C. for 15 hr.Ethyl acetate and water were added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (1 mL). N,N′-Carbonyldiimidazole (0.024 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.022 mL) were added, andthe mixture was stirred at room temperature for 1 hr. The reactionmixture was diluted with ethyl acetate, adjusted to pH 4 with 1 Mhydrochloric acid, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.022 g, 29%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.19 Hz, 3H) 1.08 (s, 3 H) 1.10(s, 3H) 1.48-1.64 (m, 2H) 1.91-2.06 (m, 1H) 2.57-3.08 (m, 6H) 3.36-3.53(m, 1H) 3.87 (s, 2H) 3.98 (s, 2H) 4.65 (s, 1H) 5.13-5.31 (m, 1H)7.18-7.26 (m, 3H) 7.28-7.39 (m, 2H) 7.46-7.59 (m, 2H) 7.61-7.74 (m, 2H)8.19 (s, 1H) 12.39 (br. s., 1H)

Example 3214-[2-(2-hydroxy-2-methylpropyl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.15 g), sodium hydrogencarbonate (0.25 g) and dimethyl sulfoxide (2 mL) was stirred at 40° C.for 30 min,4′-({4-[2-(2-hydroxy-2-methylpropyl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.085 g) was added, and the mixture was stirred at 90° C. for 15 hr.Ethyl acetate and water were added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (1 mL). N,N′-Carbonyldiimidazole (0.030 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.027 mL) were added, andthe mixture was stirred at room temperature for 1 hr. The reactionmixture was diluted with ethyl acetate, adjusted to pH 4 with 1 Mhydrochloric acid, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.032 g, 34%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.38 Hz, 3H) 1.05 (s, 6H)1.42-1.67 (m, 2H) 1.91-2.04 (m, 1H) 2.58-3.06 (m, 6H) 3.39-3.56 (m, 1H)3.91 (s, 2H) 3.98 (s, 2H) 4.65 (s, 1H) 5.09-5.33 (m, 1H) 7.17-7.26 (m,2H) 7.27-7.35 (m, 2H) 7.38 (s, 1H) 7.46-7.58 (m, 2H) 7.60-7.73 (m, 2H)8.19 (s, 1H) 12.39 (br. s., 1H)

Example 3224-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt (retention time: short)

To a solution of4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(retention time: short, 0.028 g) in tetrahydrofuran (2 mL) was added 0.1M aqueous potassium hydroxide solution (0.47 mL), and the solvent wasevaporated under reduced pressure. The residue was washed withdiisopropyl ether to give the title compound as a colorless solid (0.020g, 66%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.25 Hz, 3H) 0.99 (s, 3H) 1.03(d, J=6.22 Hz, 3H) 1.08 (s, 3H) 1.19-1.34 (m, 2H) 1.49-1.77 (m, 4H)1.92-2.15 (m, 2H) 2.41-2.74 (m, 2H) 2.87-3.02 (m, 2H) 3.26 (q, J=6.22Hz, 1H) 3.34-3.45 (m, 1H) 3.91 (s, 2H) 4.06 (s, 1H) 4.80-4.99 (m, 1H)7.13-7.26 (m, 4H) 7.30-7.42 (m, 2H) 7.43-7.53 (m, 2H) 8.17 (s, 1H)

Example 3234-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt (retention time: long)

To a solution of4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(retention time: long) (0.032 g) in tetrahydrofuran (2 mL) was added 0.1M aqueous potassium hydroxide solution (0.53 mL), and the solvent wasevaporated under reduced pressure. The residue was washed withdiisopropyl ether to give the title compound as a colorless solid (0.026g, 74%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.38 Hz, 3H) 0.99 (s, 3H) 1.03(d, J=6.06 Hz, 3H) 1.08 (s, 3H) 1.17-1.42 (m, 2H) 1.49-1.77 (m, 4H)1.93-2.19 (m, 2H) 2.45-2.73 (m, 2H) 2.88-3.00 (m, 2H) 3.24 (q, J=6.44Hz, 1H) 3.34-3.44 (m, 1H) 3.91 (s, 2H) 4.06 (s, 1H) 4.80-5.05 (m, 1H)7.14-7.25 (m, 4H) 7.27-7.39 (m, 2H) 7.41-7.52 (m, 2H) 8.16 (s, 1H)

Example 3244-{trans-4-[(5-methyl-1,3,4-oxadiazol-2-yl)methoxy]cyclohexyl}-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.45 g), sodium hydrogencarbonate (0.72 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-[(4-{trans-4-[(5-methyl-1,3,4-oxadiazol-2-yl)methoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.24 g) was added, and the mixture was stirred at 90° C. for 15 hr.Ethyl acetate and water were added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure. The residue obtained bysilica gel column chromatography was dissolved in tetrahydrofuran (3mL). N,N′-Carbonyldiimidazole (0.084 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.078 mL) were added, and themixture was stirred at room temperature for 120 hr. The reaction mixturewas diluted with ethyl acetate, adjusted to pH 4 with 1 M hydrochloricacid, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.041 g, 15%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.38 Hz, 3H) 1.21-1.44 (m, 2H)1.45-1.60 (m, 2H) 1.62-1.81 (m, 2H) 2.03-2.22 (m, 2H) 2.43-2.70 (m, 5H)2.83-3.00 (m, 2H) 3.44-3.57 (m, 1H) 3.95 (s, 2H) 4.72 (s, 2H) 4.84-5.02(m, 1H) 7.17-7.25 (m, 2H) 7.28-7.37 (m, 2H) 7.46-7.59 (m, 2H) 7.61-7.76(m, 2H) 8.18 (s, 1H) 12.38 (br. s., 1H)

Example 3256-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl-4-[trans-4-(3,3,3-trifluoro-2-hydroxypropoxy)cyclohexyl][1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.098 g), sodium hydrogencarbonate (0.15 g) and dimethyl sulfoxide (2 mL) was stirred at 40° C.for 30 min,4′-({5-oxo-7-propyl-4-[trans-4-(3,3,3-trifluoro-2-hydroxypropoxy)cyclohexyl]-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.054 g) was added, and the mixture was stirred at 90° C. for 15 hr.Ethyl acetate and water were added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (1 mL). N,N′-Carbonyldiimidazole (0.016 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.015 mL) were added, andthe mixture was stirred at room temperature for 2.5 hr.N,N′-Carbonyldiimidazole (0.016 g) and1,8-diazabicyclo[5.4.0]undec-7-ene (0.015 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, adjusted to pH 4 with 1 M hydrochloricacid, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.035 g, 58%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.38 Hz, 3H) 1.23-1.42 (m, 2H)1.46-1.60 (m, 2H) 1.62-1.78 (m, 2H) 2.03-2.21 (m, 2H) 2.52-2.69 (m, 2H)2.84-3.02 (m, 2H) 3.35-3.48 (m, 1H) 3.49-3.58 (m, 1H) 3.60-3.71 (m, 1H)3.95 (s, 2H) 3.99-4.18 (m, 1H) 4.79-5.01 (m, 1H) 6.33 (d, J=6.82 Hz, 1H)7.17-7.25 (m, 2H) 7.26-7.37 (m, 2H) 7.41-7.57 (m, 2H) 7.59-7.72 (m, 2H)8.18 (s, 1H) 12.38 (br. s., 1H)

Example 3264-[trans-4-(2-hydroxybutoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4′-({4-[trans-4-(2-hydroxybutoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.48 g), 2,6-lutidine (0.21 mL), tert-butyl(dimethyl)silyltrifluoromethanesulfonate (0.41 mL) and tetrahydrofuran (5 mL) wasstirred at room temperature for 3 hr. The reaction mixture was added to1 M hydrochloric acid, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, the obtained residue was added to a mixture ofhydroxylammonium chloride (0.93 g), sodium hydrogen carbonate (1.5 g),and dimethyl sulfoxide (5 mL), which had been stirred at 40° C. for 30min in advance, and the mixture was stirred at 90° C. for 15 hr. Ethylacetate and water were added to the reaction mixture, and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was dissolved intetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.17 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.16 mL) were added, and the mixturewas stirred at room temperature for 1 hr. Ethyl acetate and water wereadded to the reaction mixture, and the mixture was acidified with 1 Mhydrochloric acid and extracted with ethyl acetate. The organic layerwas washed with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was dissolved in tetrahydrofuran (5 mL). Tetrabutylammoniumfluoride (2.2 mL, 1.0 M tetrahydrofuran solution) was added, and themixture was stirred at 70° C. for 44 hr. The reaction mixture was addedto 1 M hydrochloric acid, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography and recrystallized (ethyl acetate-hexane) to give thetitle compound as a colorless solid (0.22 g, 42%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.87 (t, J=7.35 Hz, 3H) 0.93 (t, J=7.35 Hz,3H) 1.14-1.62 (m, 6H) 1.64-1.77 (m, 2H) 2.02-2.16 (m, 2H) 2.51-2.68 (m,2H) 2.84-3.00 (m, 2H) 3.25-3.37 (m, 3H) 3.38-3.52 (m, 1H) 3.95 (s, 2H)4.47 (d, J=4.90 Hz, 1H) 4.77-5.03 (m, 1H) 7.18-7.26 (m, 2H) 7.27-7.38(m, 2H) 7.47-7.59 (m, 2H) 7.62-7.74 (m, 2H) 8.18 (s, 1H) 12.38 (s, 1H)

Example 3274-{trans-4-[(1-hydroxycyclopropyl)methoxy]cyclohexyl}-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.39 g), sodium hydrogencarbonate (0.63 g) and dimethyl sulfoxide (4 mL) was stirred at 40° C.for 30 min,4′-[(4-{trans-4-[(1-{[tert-butyl(dimethyl)silyl]oxy}cyclopropyl)methoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.24 g) was added, and the mixture was stirred at 90° C. for 40 hr.Ethyl acetate and water were added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (0.073 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.067 mL) were added, andthe mixture was stirred at room temperature for 1 hr. The reactionmixture was diluted with ethyl acetate, adjusted to pH 4 with 1 Mhydrochloric acid, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was dissolved in tetrahydrofuran (5 mL).Tetrabutylammonium fluoride (0.94 mL, 1.0 M tetrahydrofuran solution)was added and the mixture was stirred at 70° C. for 3.5 hr. The reactionmixture was added to 1 M hydrochloric acid, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.076 g, 34%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.41-0.49 (m, 2H) 0.50-0.61 (m, 2H) 0.93 (t,J=7.38 Hz, 3H) 1.20-1.40 (m, 2H) 1.46-1.62 (m, 2H) 1.63-1.80 (m, 2H)2.06-2.22 (m, 2H) 2.52-2.67 (m, 2H) 2.87-3.01 (m, 2H) 3.34-3.42 (m, 1H)3.44 (s, 2H) 3.96 (s, 2H) 4.74-5.04 (m, 1H) 5.27 (s, 1H) 7.18-7.26 (m,2H) 7.28-7.36 (m, 2H) 7.45-7.60 (m, 2H) 7.62-7.73 (m, 2H) 8.18 (s, 1H)12.39 (s, 1H)

Example 3284-[trans-4-(2-hydroxybutoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

To a solution of4-[trans-4-(2-hydroxybutoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.050 g) in tetrahydrofuran (2 mL) was added 0.1 M aqueous potassiumhydroxide solution (0.83 mL), and the solvent was evaporated underreduced pressure. The residue was washed with diisopropyl ether to givethe title compound as a colorless solid (0.049 g, 92%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.87 (t, J=7.54 Hz, 3H) 0.94 (t, J=7.35 Hz,3H) 1.16-1.80 (m, 8H) 2.02-2.17 (m, 2H) 2.53-2.68 (m, 2H) 2.88-3.02 (m,2H) 3.22-3.37 (m, 3H) 3.37-3.49 (m, 1H) 3.92 (s, 2H) 4.46 (d, J=4.90 Hz,1H) 4.80-5.03 (m, 1H) 7.22 (s, 4H) 7.32-7.45 (m, 2H) 7.46-7.58 (m, 2H)8.17 (s, 1H)

Example 3294-{trans-4-[(1-hydroxycyclopropyl)methoxy]cyclohexyl}-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

To a solution of4-{trans-4-[(1-hydroxycyclopropyl)methoxy]cyclohexyl}-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.048 g) in tetrahydrofuran (2 mL) was added 0.1 M aqueous potassiumhydroxide solution (0.80 mL), and the solvent was evaporated underreduced pressure. The residue was washed with diisopropyl ether to givethe title compound as a colorless solid (0.043 g, 84%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.42-0.50 (m, 2H) 0.51-0.60 (m, 2H) 0.95 (t,J=7.25 Hz, 3H) 1.18-1.40 (m, 2H) 1.49-1.78 (m, 4H) 2.02-2.20 (m, 2H)2.52-2.69 (m, 2H) 2.86-3.04 (m, 2H) 3.37-3.41 (m, 1H) 3.44 (s, 2H) 3.91(s, 2H) 4.82-5.03 (m, 1H) 5.27 (s, 1H) 7.13-7.26 (m, 4H) 7.30-7.40 (m,2H) 7.41-7.54 (m, 2H) 8.17 (s, 1H)

Example 3306-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl-4-[trans-4-(3,3,3-trifluoro-2-hydroxypropoxy)cyclohexyl][1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

To a solution of6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl-4-[trans-4-(3,3,3-trifluoro-2-hydroxypropoxy)cyclohexyl][1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.021 g) in tetrahydrofuran (2 mL) was added 0.1 M aqueous potassiumhydroxide solution (0.33 mL), and the solvent was evaporated underreduced pressure. The residue was washed with diisopropyl ether to givethe title compound as a colorless solid (0.015 g, 67%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.35 Hz, 3H) 1.20-1.34 (m, 2H)1.51-1.80 (m, 4H) 2.02-2.18 (m, 2H) 2.53-2.70 (m, 2H) 2.88-3.02 (m, 2H)3.35-3.46 (m, 1H) 3.47-3.58 (m, 1H) 3.60-3.71 (m, 1H) 3.91 (s, 2H)4.02-4.18 (m, 1H) 4.79-5.04 (m, 1H) 6.32 (d, J=6.59 Hz, 1H) 7.14-7.26(m, 4H) 7.28-7.41 (m, 2H) 7.42-7.57 (m, 2H) 8.16 (s, 1H)

Example 3314-{trans-4-[(2-hydroxybut-3-en-1-yl)oxy]cyclohexyl}-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4′-[(4-{trans-4-[(2-hydroxybut-3-en-1-yl)oxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.33 g), 2,6-lutidine (0.18 mL), tert-butyl(dimethyl)silyltrifluoromethanesulfonate (0.35 mL) and tetrahydrofuran (4 mL) wasstirred at room temperature for 1 hr. The reaction mixture was added to1 M hydrochloric acid, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated sodium hydrogen carbonateand then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, the obtainedresidue was added to a mixture of hydroxylammonium chloride (0.63 g),sodium hydrogen carbonate (1.0 g), and dimethyl sulfoxide (5 mL), whichhad been stirred at 40° C. for 30 min in advance, and the mixture wasstirred at 90° C. for 20 hr. Ethyl acetate and water were added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was dissolved in tetrahydrofuran (4 mL).N,N′-Carbonyldiimidazole (0.11 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.10 mL) were added, and the mixturewas stirred at room temperature for 1 hr. Ethyl acetate and water wereadded to the reaction mixture, and the mixture was acidified with 1 Mhydrochloric acid and extracted with ethyl acetate. The organic layerwas washed with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was dissolved in tetrahydrofuran (5 mL). Tetrabutylammoniumfluoride (1.5 mL, 1.0 M tetrahydrofuran solution) was added, and themixture was stirred at 70° C. for 2 hr. The reaction mixture was addedto 1 M hydrochloric acid, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography and HPLC and recrystallized (ethyl acetate-diisopropylether) to give the title compound as a colorless solid (0.040 g, 9%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.35 Hz, 3H) 1.20-1.42 (m, 2H)1.48-1.63 (m, 2H) 1.64-1.79 (m, 2H) 2.03-2.20 (m, 2H) 2.53-2.67 (m, 2H)2.85-2.99 (m, 2H) 3.32-3.40 (m, 3H) 3.95 (s, 2H) 4.00-4.13 (m, 1H) 4.87(d, J=4.90 Hz, 1H) 4.89-4.99 (m, 1H) 5.01-5.12 (m, 1H) 5.19-5.31 (m, 1H)5.78-5.94 (m, 1H) 7.18-7.25 (m, 2H) 7.26-7.33 (m, 2H) 7.44-7.58 (m, 2H)7.60-7.72 (m, 2H) 8.18 (s, 1H) 12.36 (br. s., 1H)

Example 3324-[trans-4-(2-cyclopropyl-2-hydroxyethoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4′-({4-[trans-4-(2-cyclopropyl-2-hydroxyethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.17 g), 2,6-lutidine (0.072 mL), tert-butyl(dimethyl)silyltrifluoromethanesulfonate (0.14 mL) and tetrahydrofuran (4 mL) wasstirred at room temperature for 3 hr. The reaction mixture was added to1 M hydrochloric acid, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the obtained residue was added to a mixture ofhydroxylammonium chloride (0.32 g), sodium hydrogen carbonate (0.52 g),and dimethyl sulfoxide (5 mL), which had been stirred at 40° C. for 30min in advance, and the mixture was stirred at 90° C. for 15 hr. Ethylacetate and water were added to the reaction mixture, and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was dissolved intetrahydrofuran (4 mL). N,N′-Carbonyldiimidazole (0.060 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.055 mL) were added, and themixture was stirred at room temperature for 1 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was acidifiedwith 1 M hydrochloric acid and extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was dissolved in tetrahydrofuran (5 mL).Tetrabutylammonium fluoride (0.78 mL, 1.0 M tetrahydrofuran solution)was added, and the mixture was stirred at 70° C. for 2 hr. The reactionmixture was added to 1 M hydrochloric acid, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.11 g, 62%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.17-0.27 (m, 2H) 0.29-0.39 (m, 2H)0.73-0.87 (m, 1H) 0.92 (t, J=7.19 Hz, 3H) 1.18-1.40 (m, 2H) 1.45-1.61(m, 2H) 1.62-1.77 (m, 2H) 2.03-2.21 (m, 2H) 2.53-2.69 (m, 2H) 2.87-2.99(m, 2H) 3.01-3.13 (m, 1H) 3.33-3.51 (m, 3H) 3.96 (s, 2H) 4.47 (d, J=4.92Hz, 1H) 4.77-5.03 (m, 1H) 7.16-7.24 (m, 2H) 7.27-7.35 (m, 2H) 7.46-7.59(m, 2H) 7.62-7.74 (m, 2H) 8.18 (s, 1H) 12.37 (s, 1H)

Example 3334-{trans-4-[(2-hydroxybut-3-en-1-yl)oxy]cyclohexyl}-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

To a solution of4-{trans-4-[(2-hydroxybut-3-en-1-yl)oxy]cyclohexyl}-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.023 g) in tetrahydrofuran (2 mL) was added 0.1 M aqueous potassiumhydroxide solution (0.38 mL), and the solvent was evaporated underreduced pressure. The residue was washed with diisopropyl ether to givethe title compound as a colorless solid (0.018 g, 75%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.19 Hz, 3H) 1.18-1.37 (m, 2H)1.48-1.80 (m, 4H) 1.99-2.21 (m, 2H) 2.53-2.66 (m, 2H) 2.87-3.01 (m, 1H)3.23-3.42 (m, 4H) 3.92 (s, 2H) 4.01-4.15 (m, 1H) 4.80-4.99 (m, 2H)5.01-5.12 (m, 1H) 5.19-5.32 (m, 1H) 5.86 (ddd, J=17.42, 10.60, 4.92 Hz,1H) 7.21 (s, 4H) 7.29-7.42 (m, 2H) 7.43-7.54 (m, 2H) 8.17 (s, 1H)

Example 3344-[trans-4-(2-cyclopropyl-2-hydroxyethoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

To a solution of4-[trans-4-(2-cyclopropyl-2-hydroxyethoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.093 g) in tetrahydrofuran (2 mL) was added 0.1 M aqueous potassiumhydroxide solution (1.5 mL), and the solvent was evaporated underreduced pressure. The residue was washed with diisopropyl ether to givethe title compound as a colorless solid (0.093 g, 93%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.12-0.42 (m, 4H) 0.70-0.88 (m, 1H) 0.95 (t,J=7.19 Hz, 3H) 1.18-1.38 (m, 2H) 1.48-1.83 (m, 4H) 1.97-2.19 (m, 2H)2.53-2.70 (m, 2H) 2.86-3.00 (m, 2H) 3.02-3.14 (m, 1H) 3.21-3.51 (m, 3H)3.91 (s, 2H) 4.37-4.59 (m, 1H) 4.83-5.04 (m, 1H) 7.13-7.26 (m, 4H)7.28-7.41 (m, 2H) 7.42-7.56 (m, 2H) 8.17 (s, 1H)

Example 3356-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl-4-[trans-4-(3,3,3-trifluoro-2-hydroxy-2-methylpropoxy)cyclohexyl][1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.16 g), sodium hydrogencarbonate (0.26 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C.for 30 min,4′-({5-oxo-7-propyl-4-[trans-4-(3,3,3-trifluoro-2-hydroxy-2-methylpropoxy)cyclohexyl]-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.092 g) was added, and the mixture was stirred at 90° C. for 19 hr.Ethyl acetate and water were added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (0.031 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.028 mL) were added, andthe mixture was stirred at room temperature for 1.5 hr. The reactionmixture was diluted with ethyl acetate, 1 M hydrochloric acid was added,and the mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.063 g, 62%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.38 Hz, 3H) 1.18-1.41 (m, 5H)1.46-1.81 (m, 4H) 2.02-2.21 (m, 2H) 2.52-2.69 (m, 2H) 2.82-3.02 (m, 2H)3.28-3.42 (m, 1H) 3.43-3.49 (m, 1H) 3.51-3.60 (m, 1H) 3.95 (s, 2H)4.80-5.00 (m, 1H) 5.93 (s, 1H) 7.17-7.24 (m, 2H) 7.27-7.36 (m, 2H)7.45-7.59 (m, 2H) 7.61-7.73 (m, 2H) 8.18 (s, 1H) 12.37 (s, 1H)

Example 3364-[trans-4-(3-fluoro-2-hydroxypropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4′-({4-[trans-4-(3-fluoro-2-hydroxypropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.088 g), 2,6-lutidine (0.038 mL), tert-butyl(dimethyl)silyltrifluoromethanesulfonate (0.075 mL) and tetrahydrofuran (1 mL) wasstirred at room temperature for 2 hr. The reaction mixture was added to1 M hydrochloric acid, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, the obtained residue was added to a mixture ofhydroxylammonium chloride (0.17 g), sodium hydrogen carbonate (0.27 g),and dimethyl sulfoxide (3 mL), which had been stirred at 40° C. for 30min in advance, and the mixture was stirred at 90° C. for 12 hr. Ethylacetate and water were added to the reaction mixture, and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was dissolved intetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.032 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.029 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, adjusted to pH 4 with 1 M hydrochloricacid, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was dissolved in tetrahydrofuran (3 mL).Tetrabutylammonium fluoride (0.40 mL, 1.0 M tetrahydrofuran solution)was added, and the mixture was stirred at 70° C. for 2 hr. The reactionmixture was added to 1 M hydrochloric acid, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.061 g, 62%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.38 Hz, 3H) 1.17-1.40 (m, 2H)1.45-1.63 (m, 2H) 1.63-1.81 (m, 2H) 2.01-2.17 (m, 2H) 2.52-2.67 (m, 2H)2.85-3.03 (m, 2H) 3.33-3.39 (m, 1H) 3.42 (d, J=5.68 Hz, 2H) 3.65-3.87(m, 1H) 3.95 (s, 2H) 4.28 (ddd, J=23.10, 9.47, 3.41 Hz, 1H) 4.44 (ddd,J=23.10, 9.47, 3.41 Hz, 1H) 4.77-5.00 (m, 1H) 5.12 (d, J=5.30 Hz, 1H)7.18-7.25 (m, 2H) 7.26-7.36 (m, 2H) 7.46-7.59 (m, 2H) 7.61-7.76 (m, 2H)8.18 (s, 1H) 12.37 (s, 1H)

Example 3374-[trans-4-(3-fluoro-2-hydroxy-2-methylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.18 g), sodium hydrogencarbonate (0.30 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C.for 30 min,4′-({4-[trans-4-(3-fluoro-2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.10 g) was added, and the mixture was stirred at 90° C. for 24 hr.Ethyl acetate and water were added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.036 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.033 mL) were added, andthe mixture was stirred at room temperature for 2 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture wasneutralized with 1 M hydrochloric acid and extracted with ethyl acetate.The organic layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.078 g,70%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.19 Hz, 3H) 1.06 (d, J=2.27 Hz,3H) 1.20-1.37 (m, 2H) 1.44-1.79 (m, 4H) 2.01-2.19 (m, 2H) 2.52-2.67 (m,2H) 2.84-3.00 (m, 2H) 3.22-3.43 (m, 3H) 3.95 (s, 2H) 4.19 (d, J=47.71Hz, 2H) 4.77 (s, 1H) 4.82-5.06 (m, 1H) 7.16-7.25 (m, 2H) 7.27-7.36 (m,2H) 7.45-7.59 (m, 2H) 7.62-7.74 (m, 2H) 8.18 (s, 1H) 12.37 (s, 1H)

Example 3384-{trans-4-[(1-hydroxycyclobutyl)methoxy]cyclohexyl}-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.18 g), sodium hydrogencarbonate (0.29 g) and dimethyl sulfoxide (4 mL) was stirred at 40° C.for 30 min,4′-[(4-{trans-4-[(1-hydroxycyclobutyl)methoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.095 g) was added, and the mixture was stirred at 90° C. for 16 hr.Ethyl acetate and water were added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.034 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.031 mL) were added, andthe mixture was stirred at room temperature for 4 hr. The reactionmixture was diluted with ethyl acetate, adjusted to pH 4 with 1 Mhydrochloric acid, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.048 g, 46%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.16 Hz, 3H) 1.21-2.04 (m, 12H)2.07-2.20 (m, 2H) 2.52-2.71 (m, 2H) 2.87-3.01 (m, 2H) 3.34-3.45 (m, 3H)3.96 (s, 2H) 4.84 (s, 1H) 4.86-5.01 (m, 1H) 7.18-7.25 (m, 2H) 7.27-7.36(m, 2H) 7.45-7.59 (m, 2H) 7.61-7.73 (m, 2H) 8.18 (s, 1H) 12.30 (br. s.,1H)

Example 3394-{trans-4-[3-fluoro-2-(fluoromethyl)-2-hydroxypropoxy]cyclohexyl}-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.29 g), sodium hydrogencarbonate (0.47 g) and dimethyl sulfoxide (4 mL) was stirred at 40° C.for 30 min,4′-[(4-{trans-4-[3-fluoro-2-(fluoromethyl)-2-hydroxypropoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.16 g) was added, and the mixture was stirred at 90° C. for 24 hr andthen at room temperature for 34 hr. Ethyl acetate and water were addedto the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was dissolved in tetrahydrofuran (2mL). N,N′-Carbonyldiimidazole (0.055 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.051 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, adjusted to pH 4 with 1 M hydrochloricacid, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.10 g, 61%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.35 Hz, 3H) 1.21-1.39 (m, 2H)1.44-1.77 (m, 4H) 2.04-2.18 (m, 2H) 2.52-2.68 (m, 2H) 2.86-3.00 (m, 2H)3.26-3.40 (m, 1H) 3.45 (s, 2H) 3.95 (s, 2H) 4.36 (d, J=47.47 Hz, 4H)4.82-5.00 (m, 1 H) 5.35 (s, 1H) 7.16-7.26 (m, 2H) 7.27-7.34 (m, 2H)7.46-7.60 (m, 2H) 7.62-7.74 (m, 2H) 8.18 (s, 1H) 12.37 (s, 1H)

Example 3404-[trans-4-(3-fluoro-2-hydroxy-2-methylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

To a solution of4-[trans-4-(3-fluoro-2-hydroxy-2-methylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.052 g) in tetrahydrofuran (2 mL) was added 0.1 M aqueous potassiumhydroxide solution (0.85 mL), and the solvent was evaporated underreduced pressure. The residue was washed with diisopropyl ether to givethe title compound as a colorless solid (0.038 g, 68%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.25 Hz, 3H) 1.06 (d, J=2.07 Hz,3H) 1.19-1.38 (m, 2H) 1.47-1.84 (m, 4H) 1.98-2.17 (m, 2H) 2.52-2.67 (m,2H) 2.87-3.01 (m, 2H) 3.20-3.42 (m, 3H) 3.93 (s, 2H) 4.19 (d, J=47.85Hz, 2H) 4.77 (s, 1H) 4.81-5.01 (m, 1H) 7.16-7.27 (m, 4H) 7.34-7.47 (m,2H) 7.49-7.58 (m, 2H) 8.17 (s, 1H)

Example 3414-{trans-4-[(1-hydroxycyclobutyl)methoxy]cyclohexyl}-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

To a solution of4-{trans-4-[(1-hydroxycyclobutyl)methoxy]cyclohexyl}-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.030 g) in tetrahydrofuran (2 mL) was added 0.1 M aqueous potassiumhydroxide solution (0.49 mL), and the solvent was evaporated underreduced pressure. The residue was washed with diisopropyl ether to givethe title compound as a colorless solid (0.020 g, 63%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.35 Hz, 3H) 1.18-2.23 (m, 14H)2.53-2.67 (m, 2H) 2.89-3.01 (m, 2H) 3.33-3.43 (m, 3H) 3.93 (s, 2H) 4.83(s, 1H) 4.85-4.99 (m, 1H) 7.22 (s, 4H) 7.33-7.46 (m, 2H) 7.47-7.57 (m,2H) 8.17 (s, 1H)

Example 3424-{trans-4-[3-fluoro-2-(fluoromethyl)-2-hydroxypropoxy]cyclohexyl}-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

To a solution of4-{trans-4-[3-fluoro-2-(fluoromethyl)-2-hydroxypropoxy]cyclohexyl}-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.081 g) in tetrahydrofuran (2 mL) was added 0.1 M aqueous potassiumhydroxide solution (1.2 mL), and the solvent was evaporated underreduced pressure. The residue was washed with diisopropyl ether to givethe title compound as a colorless solid (0.063 g, 73%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.35 Hz, 3H) 1.20-1.39 (m, 2H)1.46-1.82 (m, 4H) 2.00-2.20 (m, 2H) 2.52-2.67 (m, 2H) 2.87-3.02 (m, 2H)3.33-3.40 (m, 1H) 3.45 (s, 2H) 3.93 (s, 2H) 4.36 (d, J=47.47 Hz, 4H)4.81-5.00 (m, 1H) 5.35 (s, 1H) 7.22 (s, 4H) 7.32-7.46 (m, 2H) 7.47-7.57(m, 2H) 8.17 (s, 1H)

Example 3436-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl-4-[trans-4-(tetrahydrofuran-2-ylmethoxy)cyclohexyl][1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.24 g), sodium hydrogencarbonate (0.39 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-({5-oxo-7-propyl-4-[trans-4-(tetrahydrofuran-2-ylmethoxy)cyclohexyl]-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.12 g) was added, and the mixture was stirred at 90° C. for 15 hr.Ethyl acetate and water were added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.045 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.042 mL) were added, andthe mixture was stirred at room temperature for 5 hr. The reactionmixture was diluted with ethyl acetate, adjusted to pH 4 with 1 Mhydrochloric acid, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography andHPLC to give the title compound as a colorless solid (0.062 g, 43%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.25 Hz, 3H) 1.18-1.98 (m, 10H)2.02-2.18 (m, 2H) 2.52-2.68 (m, 2H) 2.87-3.01 (m, 2H) 3.25-3.48 (m, 3H)3.56-3.66 (m, 1H) 3.68-3.80 (m, 1H) 3.83-3.93 (m, 1H) 3.95 (s, 2H)4.79-5.02 (m, 1H) 7.18-7.26 (m, 2H) 7.28-7.35 (m, 2H) 7.47-7.59 (m, 2H)7.61-7.75 (m, 2H) 8.18 (s, 1H) 12.37 (s, 1H)

Example 3444-{trans-4-[(1-hydroxycyclopentyl)methoxy]cyclohexyl}-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.050 g), sodium hydrogencarbonate (0.081 g) and dimethyl sulfoxide (2 mL) was stirred at 40° C.for 30 min,4′-[(4-{trans-4-[(1-hydroxycyclopentyl)methoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.026 g) was added, and the mixture was stirred at 90° C. for 24 hr andthen at room temperature for 58 hr. Ethyl acetate and water were addedto the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was dissolved in tetrahydrofuran (1mL). N,N′-Carbonyldiimidazole (0.010 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.0090 mL) were added, and themixture was stirred at room temperature for 5 hr. The reaction mixturewas diluted with ethyl acetate, adjusted to pH 4 with 1 M hydrochloricacid, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.0070 g, 23%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.08 (t, J=7.35 Hz, 3H) 1.34-1.89 (m,14H) 2.09-2.26 (m, 2H) 2.55-2.78 (m, 2H) 2.99-3.14 (m, 2H) 3.33-3.54 (m,3H) 3.98 (s, 2H) 4.90-5.14 (m, 1H) 7.21-7.29 (m, 2H) 7.30-7.37 (m, 2H)7.40 (dd, J=7.63, 1.04 Hz, 1H) 7.45-7.53 (m, 1H) 7.57-7.65 (m, 1H) 7.85(dd, J=7.72, 1.13 Hz, 1H) 7.91 (s, 1H)

Example 3454-[trans-4-(2-hydroxy-2-methylbutoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.11 g), sodium hydrogencarbonate (0.18 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C.for 30 min,4′-({4-[trans-4-(2-hydroxy-2-methylbutoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.060 g) was added, and the mixture was stirred at 90° C. for 24 hr andthen at room temperature for 35 hr. Ethyl acetate and water were addedto the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was dissolved in tetrahydrofuran (1mL). N,N′-Carbonyldiimidazole (0.021 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.019 mL) were added, and themixture was stirred at room temperature for 1 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was adjustedto pH 4 with 1 M hydrochloric acid and extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.049 g, 73%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.81 (t, J=7.54 Hz, 3H) 0.92 (t, J=7.35 Hz,3H) 1.02 (s, 3H) 1.21-1.32 (m, 2H) 1.37 (q, J=7.35 Hz, 2H) 1.47-1.61 (m,2H) 1.63-1.77 (m, 2H) 2.03-2.18 (m, 2H) 2.52-2.67 (m, 2H) 2.87-2.99 (m,2H) 3.15-3.26 (m, 2H) 3.27-3.37 (m, 1H) 3.95 (s, 2H) 4.06 (s, 1H)4.75-5.04 (m, 1H) 7.14-7.25 (m, 2H) 7.26-7.36 (m, 2H) 7.47-7.60 (m, 2H)7.61-7.77 (m, 2H) 8.18 (s, 1H) 12.37 (s, 1H)

Example 3466-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl-4-[trans-4-(tetrahydrofuran-2-ylmethoxy)cyclohexyl][1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

To a solution of6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl-4-[trans-4-(tetrahydrofuran-2-ylmethoxy)cyclohexyl][1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.042 g) in tetrahydrofuran (2 mL) was added 0.1 M aqueous potassiumhydroxide solution (0.68 mL), and the solvent was evaporated underreduced pressure. The residue was washed with diisopropyl ether to givethe title compound as a colorless solid (0.027 g, 62%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.19 Hz, 3H) 1.17-1.35 (m, 2H)1.45-1.96 (m, 8H) 2.00-2.17 (m, 2H) 2.52-2.68 (m, 2H) 2.87-3.02 (m, 2H)3.34-3.48 (m, 3H) 3.54-3.66 (m, 1H) 3.67-3.79 (m, 1H) 3.82-3.99 (m, 3H)4.78-5.04 (m, 1H) 7.10-7.27 (m, 4H) 7.29-7.55 (m, 4H) 8.16 (s, 1H)

Example 3474-[trans-4-(2-hydroxy-2-methylbutoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

To a solution of4-[trans-4-(2-hydroxy-2-methylbutoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.026 g) in tetrahydrofuran (2 mL) was added 0.1 M aqueous potassiumhydroxide solution (0.43 mL), and the solvent was evaporated underreduced pressure. The residue was washed with diisopropyl ether to givethe title compound as a colorless solid (0.022 g, 77%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.81 (t, J=7.57 Hz, 3H) 0.95 (t, J=7.19 Hz,3H) 1.01 (s, 3H) 1.18-1.47 (m, 4H) 1.51-1.83 (m, 4H) 1.99-2.19 (m, 2H)2.52-2.69 (m, 2H) 2.86-3.04 (m, 2H) 3.18 (d, J=9.09 Hz, 1H) 3.24 (d,J=9.09 Hz, 1H) 3.27-3.31 (m, 1H) 3.91 (s, 2H) 4.06 (s, 1H) 4.82-5.03 (m,1H) 7.14-7.27 (m, 4H) 7.29-7.54 (m, 4H) 8.16 (s, 1H)

Example 3484-[trans-4-(1-ethyl-2-hydroxy-2-methylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.23 g), sodium hydrogencarbonate (0.37 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-({4-[trans-4-(1-ethyl-2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.12 g) was added, and the mixture was stirred at 90° C. for 11 hr.Water was added to the reaction mixture, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated brine,and dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure, and the residue was dissolved in tetrahydrofuran(2 mL). N,N′-Carbonyldiimidazole (0.044 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.040 mL) were added, and themixture was stirred at room temperature for 4 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was adjustedto pH 4 with 1 M hydrochloric acid, and extracted with ethyl acetate.The organic layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.080 g,56%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.85-0.98 (m, 6H) 1.02 (s, 3H) 1.08 (s, 3H)1.13-1.79 (m, 8H) 2.01-2.23 (m, 2H) 2.52-2.65 (m, 2H) 2.86-2.98 (m, 2H)3.03 (dd, J=8.95, 2.73 Hz, 1H) 3.44-3.63 (m, 1H) 3.95 (s, 2H) 4.11 (s,1H) 4.76-5.03 (m, 1H) 7.18-7.26 (m, 2H) 7.27-7.35 (m, 2H) 7.46-7.59 (m,2H) 7.62-7.79 (m, 2H) 8.18 (s, 1H) 12.38 (s, 1 H)

Example 3494-[trans-4-(1-ethyl-2-hydroxy-2-methylpropoxy)cyclohexyl]-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.21 g), sodium hydrogencarbonate (0.34 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-({4-[trans-4-(1-ethyl-2-hydroxy-2-methylpropoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.11 g) was added, and the mixture was stirred at 90° C. for 11 hr.Water was added to the reaction mixture, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated brine,and dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure, and the residue was dissolved in tetrahydrofuran(2 mL). N,N′-Carbonyldiimidazole (0.040 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.037 mL) were added, and themixture was stirred at room temperature for 4 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was adjustedto pH 4 with 1 M hydrochloric acid, and extracted with ethyl acetate.The organic layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.079 g,60%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.87-0.98 (m, 6H) 1.02 (s, 3H) 1.08 (s, 3H)1.13-1.77 (m, 8H) 2.04-2.19 (m, 2H) 2.35 (s, 3H) 2.52-2.64 (m, 2H)2.82-2.95 (m, 2H) 3.04 (dd, J=9.14, 2.73 Hz, 1H) 3.42-3.63 (m, 1H) 3.93(s, 2H) 4.12 (s, 1H) 4.71-4.99 (m, 1H) 7.17-7.24 (m, 2H) 7.26-7.34 (m,2H) 7.46-7.60 (m, 2H) 7.62-7.75 (m, 2H) 12.38 (s, 1H)

Example 3504-[trans-4-(1-ethyl-2-hydroxy-2-methylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

To a solution of4-[trans-4-(1-ethyl-2-hydroxy-2-methylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.058 g) in tetrahydrofuran (2 mL) was added 0.1 M aqueous potassiumhydroxide solution (0.93 mL), and the solvent was evaporated underreduced pressure. The residue was washed with diisopropyl ether to givethe title compound as a colorless solid (0.054 g, 87%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.87-0.99 (m, 6H) 1.02 (s, 3H) 1.08 (s, 3H)1.13-1.78 (m, 8H) 2.03-2.21 (m, 2H) 2.52-2.68 (m, 2H) 2.90-2.99 (m, 2H)3.03 (dd, J=9.04, 2.64 Hz, 1H) 3.41-3.61 (m, 1H) 3.91 (s, 2H) 4.11 (s,1H) 4.74-5.03 (m, 1H) 7.13-7.24 (m, 4H) 7.26-7.54 (m, 4H) 8.16 (s, 1H)

Example 3514-[trans-4-(1-ethyl-2-hydroxy-2-methylpropoxy)cyclohexyl]-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

To a solution of4-[trans-4-(1-ethyl-2-hydroxy-2-methylpropoxy)cyclohexyl]-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.057 g) in tetrahydrofuran (2 mL) was added 0.1 M aqueous potassiumhydroxide solution (0.90 mL), and the solvent was evaporated underreduced pressure. The residue was washed with diisopropyl ether to givethe title compound as a colorless solid (0.053 g, 87%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.85-0.99 (m, 6H) 1.02 (s, 3H) 1.08 (s, 3H)1.12-1.79 (m, 8H) 2.05-2.21 (m, 2H) 2.35 (s, 3H) 2.52-2.66 (m, 2H)2.81-2.97 (m, 2H) 3.04 (dd, J=9.04, 2.64 Hz, 1H) 3.44-3.61 (m, 1H) 3.88(s, 2H) 4.12 (s, 1H) 4.70-4.99 (m, 1H) 7.11-7.25 (m, 4H) 7.26-7.56 (m,4H)

Example 3524-[trans-4-(3,3-difluoro-2-hydroxypropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.18 g), sodium hydrogencarbonate (0.24 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C.for 30 min,4′-({4-[trans-4-(2-{[tert-butyl(dimethyl)silyl]oxy}-3,3-difluoropropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.12 g) was added, and the mixture was stirred at 90° C. for 21 hr.Ethyl acetate and water were added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.035 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.032 mL) were added, andthe mixture was stirred at room temperature for 2 hr. Thereafter,tetrabutylammonium fluoride (0.44 mL, 1.0 M tetrahydrofuran solution)was added, and the mixture was stirred at 70° C. for 2 hr. To thereaction mixture was added 1 M hydrochloric acid, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.080 g, 73%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.35 Hz, 3H) 1.21-1.39 (m, 2H)1.45-1.81 (m, 4H) 2.03-2.20 (m, 2H) 2.51-2.68 (m, 2H) 2.86-3.00 (m, 2H)3.33-3.44 (m, 1H) 3.45-3.60 (m, 2H) 3.65-3.85 (m, 1H) 3.96 (s, 2H)4.74-5.09 (m, 1H) 5.63 (d, J=6.22 Hz, 1H) 5.89 (dt, J=55.53, 3.67 Hz,1H) 7.18-7.25 (m, 2H) 7.27-7.36 (m, 2H) 7.47-7.60 (m, 2H) 7.61-7.77 (m,2H) 8.18 (s, 1H) 12.38 (s, 1H)

Example 3534-[trans-4-(3,3-difluoro-2-hydroxypropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

To a solution of4-[trans-4-(3,3-difluoro-2-hydroxypropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.055 g) in tetrahydrofuran (2 mL) was added 0.1 M aqueous potassiumhydroxide solution (0.89 mL), and the solvent was evaporated underreduced pressure. The residue was washed with diisopropyl ether to givethe title compound as a colorless solid (0.055 g, 94%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.96 (t, J=7.35 Hz, 3H) 1.17-1.41 (m, 2H)1.52-1.82 (m, 4H) 2.03-2.18 (m, 2H) 2.52-2.68 (m, 2H) 2.89-3.03 (m, 2H)3.34-3.42 (m, 1H) 3.44-3.63 (m, 2H) 3.66-3.84 (m, 1H) 3.91 (s, 2H)4.78-5.01 (m, 1H) 5.63 (d, J=6.03 Hz, 1H) 5.89 (dt, J=55.53, 3.67 Hz,1H) 7.13-7.51 (m, 8H) 8.16 (s, 1H)

Example 3544-[trans-4-(3-fluoro-2-hydroxy-2-methylpropoxy)cyclohexyl]-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.17 g), sodium hydrogencarbonate (0.27 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C.for 30 min,4′-({4-[trans-4-(3-fluoro-2-hydroxy-2-methylpropoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.094 g) was added, and the mixture was stirred at 90° C. for 14 hr.Ethyl acetate and water were added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (1 mL). N,N′-Carbonyldiimidazole (0.033 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.030 mL) were added, andthe mixture was stirred at room temperature for 1 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was acidifiedwith 1 M hydrochloric acid and extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.066 g, 63%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.38 Hz, 3H) 1.06 (d, J=2.27 Hz,3H) 1.18-1.39 (m, 2H) 1.44-1.77 (m, 4H) 2.02-2.18 (m, 2H) 2.35 (s, 3H)2.52-2.67 (m, 2H) 2.81-2.97 (m, 2H) 3.19-3.43 (m, 3H) 3.93 (s, 2H) 4.19(d, J=47.71 Hz, 2H) 4.78 (s, 1H) 4.80-4.97 (m, 1H) 7.18-7.25 (m, 2H)7.26-7.35 (m, 2H) 7.44-7.59 (m, 2H) 7.61-7.76 (m, 2H) 12.37 (s, 1H)

Example 3554-[trans-4-(1-ethyl-2-hydroxy-2-methylpropoxy)cyclohexyl]-6-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.37 g), sodium hydrogencarbonate (0.59 g, and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-({4-[trans-4-(1-ethyl-2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)-3′-fluorobiphenyl-2-carbonitrile(0.20 g) was added, and the mixture was stirred at 90° C. for 24 hr andthen at room temperature for 40 hr. Ethyl acetate and water were addedto the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was dissolved in tetrahydrofuran (2mL). N,N′-Carbonyldiimidazole (0.069 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.064 mL) were added, and themixture was stirred at room temperature for 1 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was acidifiedwith 1 M hydrochloric acid and extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.16 g, 73%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.38 Hz, 6H) 1.01 (s, 3H) 1.08(s, 3H) 1.12-1.76 (m, 8H) 2.02-2.21 (m, 2H) 2.52-2.68 (m, 2H) 2.83-2.98(m, 2H) 3.03 (dd, J=9.09, 2.65 Hz, 1H) 3.42-3.64 (m, 1H) 3.94 (s, 2H)4.10 (s, 1H) 4.74-4.98 (m, 1H) 6.99 (dd, J=8.14, 1.70 Hz, 1H) 7.16 (dd,J=11.17, 1.70 Hz, 1H) 7.20-7.32 (m, 1H) 7.49-7.63 (m, 2H) 7.64-7.74 (m,2H) 8.19 (s, 1H) 12.45 (s, 1H)

Example 3564-{trans-4-[(1-hydroxycyclobutyl)methoxy]cyclohexyl}-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.18 g), sodium hydrogencarbonate (0.29 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-[(4-{trans-4-[(1-hydroxycyclobutyl)methoxy]cyclohexyl}-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.098 g) was added, and the mixture was stirred at 90° C. for 24 hr andthen at room temperature for 38 hr. Ethyl acetate and water were addedto the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was dissolved in tetrahydrofuran (1mL). N,N′-Carbonyldiimidazole (0.028 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.031 mL) were added, and themixture was stirred at room temperature for 30 min. Ethyl acetate andwater were added to the reaction mixture, and the mixture was adjustedto pH 4 with 1 M hydrochloric acid, and extracted with ethyl acetate.The organic layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.034 g,32%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.35 Hz, 3H) 1.20-2.05 (m, 12H)2.09-2.21 (m, 2H) 2.35 (s, 3H) 2.52-2.68 (m, 2H) 2.81-2.97 (m, 2H)3.33-3.44 (m, 3H) 3.93 (s, 2H) 4.77-4.97 (m, 2H) 7.18-7.25 (m, 2H)7.26-7.34 (m, 2H) 7.47-7.59 (m, 2H) 7.61-7.75 (m, 2H) 12.37 (s, 1H)

Example 3574-[trans-4-(3-fluoro-2-hydroxy-2-methylpropoxy)cyclohexyl]-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

To a solution of4-[trans-4-(3-fluoro-2-hydroxy-2-methylpropoxy)cyclohexyl]-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.041 g) in tetrahydrofuran (2 mL) was added 0.1 M aqueous potassiumhydroxide solution (0.65 mL), and the solvent was evaporated underreduced pressure. The residue was washed with diisopropyl ether to givethe title compound as a colorless solid (0.037 g, 85%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.38 Hz, 3H) 1.06 (d, J=2.27 Hz,3H) 1.18-1.42 (m, 2H) 1.48-1.79 (m, 4H) 2.02-2.16 (m, 2H) 2.35 (s, 3H)2.52-2.66 (m, 2H) 2.82-2.98 (m, 2H) 3.21-3.42 (m, 3H) 3.88 (s, 2H) 4.23(d, J=48.09 Hz, 2H) 4.77 (s, 1H) 4.80-4.97 (m, 1H) 7.11-7.25 (m, 4H)7.26-7.53 (m, 4H)

Example 3584-[trans-4-(1-ethyl-2-hydroxy-2-methylpropoxy)cyclohexyl]-6-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

To a solution of4-[trans-4-(1-ethyl-2-hydroxy-2-methylpropoxy)cyclohexyl]-6-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.11 g) in tetrahydrofuran (2 mL) was added 0.1 M aqueous potassiumhydroxide solution (1.8 mL), and the solvent was evaporated underreduced pressure. The residue was washed with diisopropyl ether to givethe title compound as a colorless solid (0.11 g, 89%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.87-0.98 (m, 6H) 1.01 (s, 3H) 1.08 (s, 3H)1.13-1.80 (m, 8H) 1.98-2.21 (m, 2H) 2.52-2.66 (m, 2H) 2.86-2.98 (m, 2H)3.03 (dd, J=8.90, 2.08 Hz, 1H) 3.42-3.61 (m, 1H) 3.90 (s, 2H) 4.10 (s,1H) 4.77-5.02 (m, 1H) 6.96-7.20 (m, 3H) 7.29-7.57 (m, 4H) 8.17 (s, 1H)

Example 3594-{trans-4-[(1-hydroxycyclobutyl)methoxy]cyclohexyl}-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

To a solution of4-{trans-4-[(1-hydroxycyclobutyl)methoxy]cyclohexyl}-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.019 g) in tetrahydrofuran (2 mL) was added 0.1 M aqueous potassiumhydroxide solution (0.30 mL), and the solvent was evaporated underreduced pressure. The residue was washed with diisopropyl ether to givethe title compound as a colorless solid (0.016 g, 80%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.19 Hz, 3H) 1.20-2.24 (m, 14H)2.35 (s, 3H) 2.51-2.68 (m, 2H) 2.83-2.97 (m, 2H) 3.32-3.43 (m, 3H) 3.88(s, 2H) 4.78-4.97 (m, 2H) 7.11-7.24 (m, 4H) 7.25-7.50 (m, 4H)

Example 3606-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-2-methyl-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.70 g), sodium hydrogencarbonate (1.1 g) and dimethyl sulfoxide (6 mL) was stirred at 40° C.for 30 min,3′-fluoro-4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.39 g) was added and the mixture was stirred at 90° C. for 24 hr andthen at room temperature for 38 hr. Ethyl acetate and water were addedto the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was dissolved in tetrahydrofuran (4mL). N,N′-Carbonyldiimidazole (0.13 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.12 mL) were added, and the mixturewas stirred at room temperature for 1 hr. Ethyl acetate and water wereadded to the reaction mixture, and the mixture was acidified with 1 Mhydrochloric acid and extracted with ethyl acetate. The organic layerwas washed with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.30 g, 69%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.35 Hz, 3H) 1.07 (s, 6H)1.20-1.41 (m, 2H) 1.45-1.77 (m, 4H) 2.01-2.22 (m, 2H) 2.36 (s, 3H)2.52-2.66 (m, 2H) 2.78-2.99 (m, 2H) 3.20 (s, 2H) 3.23-3.31 (m, 1H) 3.91(s, 2H) 4.23 (s, 1H) 4.72-5.00 (m, 1H) 6.99 (dd, J=7.91, 1.70 Hz, 1H)7.10-7.31 (m, 2H) 7.48-7.63 (m, 2H) 7.65-7.76 (m, 2H) 12.45 (s, 1H)

Example 3616-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-2-methyl-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

To a solution of6-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-2-methyl-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.093 g) in tetrahydrofuran (2 mL) was added 0.1 M aqueous potassiumhydroxide solution (1.4 mL), and the solvent was evaporated underreduced pressure. The residue was washed with diisopropyl ether to givethe title compound as a colorless solid (0.083 g, 83%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.25 Hz, 3H) 1.06 (s, 6H)1.18-1.38 (m, 2H) 1.49-1.78 (m, 4H) 1.98-2.22 (m, 2H) 2.36 (s, 3H)2.52-2.68 (m, 2H) 2.81-3.00 (m, 2H) 3.20 (s, 2H) 3.24-3.31 (m, 1H) 3.87(s, 2H) 4.23 (s, 1H) 4.69-4.99 (m, 1H) 6.88-7.17 (m, 3H) 7.24-7.57 (m,4H)

Example 3626-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-(trans-4-{[1-(1-hydroxy-1-methylethyl)cyclopropyl]oxy}cyclohexyl)-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.059 g), sodium hydrogencarbonate (0.094 g) and dimethyl sulfoxide (2 mL) was stirred at 40° C.for 30 min,3′-fluoro-4′-{[4-(trans-4-{[1-(1-hydroxy-1-methylethyl)cyclopropyl]oxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.032 g) was added and the mixture was stirred at 90° C. for 24 hr andthen at room temperature for 40 hr. Ethyl acetate and water were addedto the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was dissolved in tetrahydrofuran (1mL). N,N′-Carbonyldiimidazole (0.011 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.010 mL) were added, and themixture was stirred at room temperature for 30 min. Ethyl acetate andwater were added to the reaction mixture, and the mixture was acidifiedwith 1 M hydrochloric acid and extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.017 g, 47%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.55-0.66 (m, 2H) 0.67-0.78 (m, 2H) 0.93 (t,J=7.19 Hz, 3H) 1.14 (s, 6H) 1.21-1.39 (m, 2 H) 1.46-1.74 (m, 4H)1.88-2.06 (m, 2H) 2.53-2.69 (m, 2H) 2.83-2.98 (m, 2H) 3.41-3.63 (m, 1H)3.93 (s, 2H) 4.20 (s, 1H) 4.72-4.96 (m, 1H) 6.99 (d, J=7.95 Hz, 1H)7.09-7.33 (m, 2H) 7.50-7.63 (m, 2H) 7.65-7.79 (m, 2H) 8.19 (s, 1H) 12.45(br. s., 1H)

Example 3634-(trans-4-{[1-(1-hydroxy-1-methylethyl)cyclopropyl]oxy}cyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.092 g), sodium hydrogencarbonate (0.14 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C.for 30 min,4′-{[4-(trans-4-{[1-(1-hydroxy-1-methylethyl)cyclopropyl]oxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.049 g) was added and the mixture was stirred at 90° C. for 24 hr andthen at room temperature for 38 hr. Ethyl acetate and water were addedto the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was dissolved in tetrahydrofuran (1mL). N,N′-Carbonyldiimidazole (0.018 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.017 mL) were added, and themixture was stirred at room temperature for 45 min. Ethyl acetate andwater were added to the reaction mixture, and the mixture was acidifiedwith 1 M hydrochloric acid and extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.025 g, 45%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.59-0.67 (m, 2H) 0.68-0.77 (m, 2H) 0.92 (t,J=7.35 Hz, 3H) 1.14 (s, 6H) 1.20-1.71 (m, 6H) 1.93-2.07 (m, 2H)2.52-2.68 (m, 2H) 2.85-2.99 (m, 2 H) 3.41-3.64 (m, 1H) 3.95 (s, 2H) 4.21(s, 1H) 4.73-4.98 (m, 1H) 7.15-7.26 (m, 2H) 7.27-7.37 (m, 2H) 7.46-7.60(m, 2H) 7.62-7.78 (m, 2H) 8.17 (s, 1H) 12.37 (br. s., 1H)

Example 3644-{trans-4-[3-fluoro-2-(fluoromethyl)-2-hydroxy-1-methylpropoxy]cyclohexyl}-6-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of3′-fluoro-4′-{[4-(trans-4-{1-[2-(fluoromethyl)oxiran-2-yl]ethoxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.079 g), tetrabutylammonium dihydrogen trifluoride (0.12 g) andchlorobenzene (0.5 mL) was stirred at 120° C. for 24 hr.Tetrabutylammonium dihydrogen trifluoride (0.12 g) was further added,and the mixture was further stirred at 120° C. for 3 days. The reactionmixture was purified by silica gel column chromatography, the obtainedresidue was added to a mixture of hydroxylammonium chloride (0.066 g),sodium hydrogen carbonate (0.10 g), and dimethyl sulfoxide (3 mL), whichhad been stirred at 40° C. for 30 min in advance, and the mixture wasstirred at 90° C. for 48 hr. Ethyl acetate and water were added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was dissolved in tetrahydrofuran (1 mL).N,N′-Carbonyldiimidazole (0.012 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.011 mL) were added, and themixture was stirred at room temperature for 2 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was acidifiedwith 1 M hydrochloric acid and extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography andHPLC to give the title compound as a colorless solid (0.016 g, 17%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.35 Hz, 3H) 1.04-1.78 (m, 9H)1.91-2.18 (m, 2H) 2.52-2.70 (m, 2H) 2.87-3.01 (m, 2H) 3.35-3.47 (m, 1H)3.54-3.71 (m, 1H) 3.93 (s, 2H) 4.21-4.54 (m, 4H) 4.75-4.99 (m, 1H) 5.21(s, 1H) 6.90-7.34 (m, 3H) 7.40-7.74 (m, 4H) 8.19 (s, 1H) 12.47 (br. s.,1H)

Example 3656-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[cis-3-(2-hydroxy-2-methylpropoxy)cyclobutyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.34 g), sodium hydrogencarbonate (0.55 g) and dimethyl sulfoxide (4 mL) was stirred at 40° C.for 30 min,3′-fluoro-4′-({4-[cis-3-(2-hydroxy-2-methylpropoxy)cyclobutyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.17 g) was added, and the mixture was stirred at 90° C. for 15 hr.Ethyl acetate and water were added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.064 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.059 mL) were added, andthe mixture was stirred at room temperature for 1 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was acidifiedwith 1 M hydrochloric acid and extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.13 g, 70%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.38 Hz, 3H) 1.09 (s, 6H)1.42-1.76 (m, 2H) 2.53-2.70 (m, 2H) 2.84-3.07 (m, 4H) 3.11 (s, 2H)3.75-3.86 (m, 1H) 3.93 (s, 2H) 4.29 (s, 1H) 4.79-5.05 (m, 1H) 6.89-7.04(m, 1H) 7.09-7.35 (m, 2 H) 7.46-7.78 (m, 4H) 8.21 (s, 1H) 12.46 (br. s.,1H)

Example 3666-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[cis-3-(2-hydroxy-2-methylpropoxy)cyclobutyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

To a solution of6-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[cis-3-(2-hydroxy-2-methylpropoxy)cyclobutyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.051 g) in tetrahydrofuran (2 mL) was added 0.1 M aqueous potassiumhydroxide solution (0.86 mL), and the solvent was evaporated underreduced pressure. The residue was washed with diisopropyl ether to givethe title compound as a colorless solid (0.045 g, 84%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.25 Hz, 3H) 1.09 (s, 6H)1.49-1.74 (m, 2H) 2.54-2.67 (m, 2H) 2.79-3.07 (m, 4H) 3.11 (s, 2H)3.66-3.85 (m, 1H) 3.89 (s, 2H) 4.31 (s, 1H) 4.70-5.09 (m, 1H) 6.93-7.24(m, 3H) 7.25-7.64 (m, 4H) 8.20 (s, 1H)

Example 3676-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-3-(2-hydroxy-2-methylpropoxy)cyclobutyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.13 g), sodium hydrogencarbonate (0.21 g) and dimethyl sulfoxide (4 mL) was stirred at 40° C.for 30 min,3′-fluoro-4′-({4-[trans-3-(2-hydroxy-2-methylpropoxy)cyclobutyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.066 g) was added, and the mixture was stirred at 90° C. for 14 hr.Ethyl acetate and water were added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (1 mL). N,N′-Carbonyldiimidazole (0.025 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.023 mL) were added, andthe mixture was stirred at room temperature for 2 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was acidifiedwith 1 M hydrochloric acid and extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.054 g, 73%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.35 Hz, 3H) 1.11 (s, 6H)1.42-1.67 (m, 2H) 2.21-2.38 (m, 2H) 2.86-2.97 (m, 2H) 3.09 (s, 2H)3.11-3.25 (m, 2H) 3.93 (s, 2H) 4.21-4.31 (m, 1H) 4.33 (s, 1H) 5.49-5.78(m, 1H) 6.99 (dd, J=7.91, 1.70 Hz, 1H) 7.10-7.32 (m, 2H) 7.49-7.63 (m,2H) 7.64-7.76 (m, 2H) 8.22 (s, 1H) 12.46 (s, 1H)

Example 3686-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-2-methylpropoxy)-4-methylcyclohexyl]-2-methyl-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.34 g), sodium hydrogencarbonate (0.56 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,3′-fluoro-4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)-4-methylcyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.19 g) was added, and the mixture was stirred at 90° C. for 14 hr.Ethyl acetate and water were added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.065 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.060 mL) were added, andthe mixture was stirred at room temperature for 2 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was acidifiedwith 1 M hydrochloric acid and extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography andrecrystallized (ethyl acetate-hexane) to give the title compound as acolorless solid (0.092 g, 43%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.35 Hz, 3H) 1.06 (s, 6H) 1.30(s, 3H) 1.40-1.87 (m, 8H) 2.37 (s, 3H) 2.54-2.76 (m, 2H) 2.79-2.96 (m,2H) 3.12 (s, 2H) 3.92 (s, 2H) 4.14 (s, 1H) 4.73-4.98 (m, 1H) 6.99 (dd,J=7.91, 1.70 Hz, 1H) 7.10-7.27 (m, 2H) 7.50-7.62 (m, 2H) 7.63-7.78 (m,2H) 12.45 (s, 1H)

Example 3696-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-3-(2-hydroxy-2-methylpropoxy)cyclobutyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

To a solution of6-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-3-(2-hydroxy-2-methylpropoxy)cyclobutyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.054 g) in tetrahydrofuran (2 mL) was added 0.1 M aqueous potassiumhydroxide solution (0.91 mL), and the solvent was evaporated underreduced pressure. The residue was washed with diisopropyl ether to givethe title compound as a colorless solid (0.032 g, 55%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.35 Hz, 3H) 1.11 (s, 6H)1.54-1.70 (m, 2H) 2.20-2.39 (m, 2H) 2.84-3.02 (m, 2H) 3.09 (s, 2H)3.11-3.26 (m, 2H) 3.89 (s, 2H) 4.17-4.47 (m, 2H) 5.55-5.81 (m, 1H)6.95-7.20 (m, 3H) 7.26-7.56 (m, 4H) 8.21 (s, 1H)

Example 3706-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-2-methylpropoxy)-4-methylcyclohexyl]-2-methyl-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

To a solution of6-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-2-methylpropoxy)-4-methylcyclohexyl]-2-methyl-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.036 g) in tetrahydrofuran (2 mL) was added 0.1 M aqueous potassiumhydroxide solution (0.56 mL), and the solvent was evaporated underreduced pressure. The residue was washed with diisopropyl ether to givethe title compound as a colorless solid (0.022 g, 59%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.25 Hz, 3H) 1.05 (s, 6H) 1.30(s, 3H) 1.40-1.88 (m, 8H) 2.36 (s, 3H) 2.55-2.75 (m, 2H) 2.82-2.96 (m,2H) 3.12 (s, 2H) 3.88 (s, 2H) 4.14 (s, 1H) 4.72-5.04 (m, 1H) 6.89-7.16(m, 3H) 7.25-7.55 (m, 4H)

Example 3716-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-{trans-4-[1-(1-hydroxycyclobutyl)ethoxy]cyclohexyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (2.7 g), sodium hydrogencarbonate (4.3 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,3′-fluoro-4′-[(4-{trans-4-[1-(1-hydroxycyclobutyl)ethoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(1.5 g) was added, and the mixture was stirred at 90° C. for 16 hr.Ethyl acetate and water were added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.50 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.46 mL) were added, andthe mixture was stirred at room temperature for 2 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was acidifiedwith 1 M hydrochloric acid and extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (1.3 g, 81%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.19 Hz, 3H) 1.01 (d, J=6.06 Hz,3H) 1.22-1.92 (m, 10H) 1.99-2.22 (m, 4H) 2.53-2.70 (m, 2H) 2.81-3.04 (m,2H) 3.34-3.46 (m, 2H) 3.94 (s, 2H) 4.64 (s, 1H) 4.79-5.00 (m, 1H) 6.99(dd, J=7.95, 1.89 Hz, 1H) 7.09-7.30 (m, 2H) 7.50-7.63 (m, 2 H) 7.64-7.76(m, 2H) 8.19 (s, 1H) 12.44 (s, 1H)

Example 3726-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-{trans-4-[1-(1-hydroxycyclobutyl)ethoxy]cyclohexyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

To a solution of6-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-{trans-4-[1-(1-hydroxycyclobutyl)ethoxy]cyclohexyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(1.3 g) in tetrahydrofuran (10 mL) was added 8M aqueous potassiumhydroxide solution (0.26 mL), and the solvent was evaporated underreduced pressure. The residue was washed with diisopropyl ether to givethe title compound as a colorless solid (1.3 g, 93%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.88-1.07 (m, 6H) 1.15-2.22 (m, 14H)2.53-3.06 (m, 4H) 3.34-3.48 (m, 2H) 3.90 (s, 2H) 4.64 (br. s., 1H)4.79-5.00 (m, 1H) 6.94-7.18 (m, 3H) 7.26-7.57 (m, 4H) 8.18 (s, 1H)

Example 3734-(1-benzylpiperidin-4-yl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.44 g), sodium hydrogencarbonate (2.32 g) and dimethyl sulfoxide (15 mL) was stirred at 50° C.for 30 min, a solution of4′-{[4-(1-benzylpiperidin-4-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(749 mg) in dimethyl sulfoxide (3 mL) was added, and the mixture wasstirred at 90° C. for 17 hr. The reaction mixture was diluted with ethylacetate, washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was dissolved in tetrahydrofuran (10 mL).N,N′-Carbonyldiimidazole (269 mg) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 mL) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel chromatography[eluent: hexane/ethyl acetate=50/50→10/90 (volume ratio)], andcrystallized from a mixture of ethyl acetate and diisopropyl ether togive the title compound as colorless crystals (133 mg, 16%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.2 Hz, 3H), 1.50-1.65 (m, 4H),2.08-2.20 (m, 2H), 2.70-3.00 (m, 6H), 3.56 (s, 2H), 3.95 (s, 2H),4.88-5.00 (m, 1H), 7.20 (d, J=8.1 Hz, 2H), 7.29 (d, J=8.1 Hz, 2H),7.33-7.34 (m, 5H), 7.45-7.54 (m, 2H), 7.61-7.68 (m, 2H), 8.18 (s, 1H),12.20 (br s, 1H).

Example 3744-(1-ethylpiperidin-4-yl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (313 mg), sodium hydrogencarbonate (504 mg) and dimethyl sulfoxide (3 mL) was stirred at 60° C.for 30 min, a solution of4′-{[4-(1-ethylpiperidin-4-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(145 mg) in dimethyl sulfoxide (2 mL) was added, and the mixture wasstirred at 90° C. for 17 hr. The reaction mixture was diluted with ethylacetate, washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was dissolved in tetrahydrofuran (10 mL).N,N′-Carbonyldiimidazole (58 mg) and then1,8-diazabicyclo[5.4.0]undec-7-ene (55 mg) were added, and the mixturewas stirred at room temperature for 15 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel chromatography[eluent: methanol/ethyl acetate=10/90→30/70 (volume ratio)] andcrystallized from acetonitrile to give the title compound as colorlesscrystals (57 mg, 35%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.2 Hz, 3H), 1.24 (t, J=7.2 Hz,3H), 1.51-1.59 (m, 2H), 1.95-1.99 (m, 2H), 2.91-3.20 (m, 8H), 3.48-3.62(m, 2H), 3.97 (s, 2H), 5.15-5.25 (m, 1H), 7.21 (d, J=8.1 Hz, 2H), 7.32(d, J=8.1 Hz, 2H), 7.47-7.57 (m, 2H), 7.64-7.71 (m, 2H), 8.23 (s, 1H),12.39 (br s, 1H).

Example 3756-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl-4-[1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl][1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (615 mg), sodium hydrogencarbonate (911 mg) and dimethyl sulfoxide (6 mL) was stirred at 60° C.for 30 min, a solution of4′-({5-oxo-7-propyl-4-[1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl]-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(317 mg) in dimethyl sulfoxide (3 mL) was added, and the mixture wasstirred at 90° C. for 16 hr. The reaction mixture was diluted with ethylacetate, washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was dissolved in tetrahydrofuran (5 mL).N,N′-Carbonyldiimidazole (115 mg) and then1,8-diazabicyclo[5.4.0]undec-7-ene (108 mg) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel chromatography[eluent: methanol/ethyl acetate=5/95→30/70 (volume ratio)] andcrystallized from acetonitrile to give the title compound as colorlesscrystals (108 mg, 31%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=6.9 Hz, 3H), 1.52-2.12 (m, 8H),2.94-3.98 (m, 15H), 5.22 (br s, 1H), 7.21 (d, J=7.8 Hz, 2H), 7.32 (d,J=7.8 Hz, 2H), 7.47-7.57 (m, 2H), 7.64-7.68 (m, 2H), 9.85 (br s, 1H),12.47 (br s, 1H).

Example 3764-[4-(1-hydroxy-1-methylethyl)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (208 mg), sodium hydrogencarbonate (336 mg) and dimethyl sulfoxide (3 mL) was stirred at 60° C.for 30 min, a solution of4′-({4-[4-(1-hydroxy-1-methylethyl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(100 mg) in dimethyl sulfoxide (1 mL) was added, and the mixture wasstirred at 90° C. for 16 hr. The reaction mixture was diluted with ethylacetate, washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was dissolved in tetrahydrofuran (8 mL).N,N′-Carbonyldiimidazole (39 mg) and then1,8-diazabicyclo[5.4.0]undec-7-ene (37 mg) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel chromatography[eluent: hexane/ethyl acetate=65/35→35/65 (volume ratio)] to give thetitle compound as a colorless amorphous compound (37 mg, 33%).

¹H NMR (300 MHz, CDCl₃) δ 1.07 (t, J=7.5 Hz, 3H), 1.17 (s, 6H),1.23-1.32 (m, 1H), 1.40-1.52 (m, 1H), 1.62-1.82 (m, 6H), 1.97-2.01 (m,2H), 2.55-2.69 (m, 2H), 3.02-3.08 (m, 2H), 3.97 (s, 2H), 4.91-5.02 (m,1H), 7.25 (d, J=8.1 Hz, 2H), 7.32 (d, J=8.1 Hz, 2H), 7.39-7.42 (m, 1H),7.45-7.50 (m, 1H), 7.56-7.62 (m, 1H), 7.80-7.83 (m, 1H), 7.90 (s, 1H),8.19 (br s, 1H).

Example 3776-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl-4-[1-(tetrahydro-2H-pyran-4-ylcarbonyl)piperidin-4-yl][1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (967 mg), sodium hydrogencarbonate (1.68 g) and dimethyl sulfoxide (9 mL) was stirred at 60° C.for 30 min,4′-({5-oxo-7-propyl-4-[1-(tetrahydro-2H-pyran-4-ylcarbonyl)piperidin-4-yl]-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(518 mg, dimethyl sulfoxide (3 mL) solution) was added, and the mixturewas stirred at 90° C. for 16 hr. The reaction mixture was diluted withethyl acetate, washed with water and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was dissolved in tetrahydrofuran (6mL). N,N′-Carbonyldiimidazole (178 mg) and then1,8-diazabicyclo[5.4.0]undec-7-ene (167 mg) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel chromatography[eluent: methanol/ethyl acetate=5/95→30/70 (volume ratio)] andcrystallized from acetonitrile to give the title compound as colorlesscrystals (253 mg, 44%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.5 Hz, 3H), 1.53-1.79 (m, 8H),2.45-2.70 (m, 3H), 2.90-2.96 (m, 3H), 3.12-3.19 (m, 1H), 3.39 (br s,2H), 3.85 (br s, 2H), 3.96 (s, 2H), 4.14 (br d, J=12.3 Hz, 1H), 4.57 (brd, J=12.3 Hz, 1H), 5.11-5.21 (m, 1H), 7.21 (d, J=8.4, 2H), 7.31 (d,J=8.4 Hz, 2H), 7.48-7.56 (m, 2H), 7.63-7.70 (m, 2H), 8.17 (s, 1H), 12.37(s, 1H).

Example 3784-[1-(2-hydroxyethyl)piperidin-4-yl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (417 mg), sodium hydrogencarbonate (672 mg) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-({4-[1-(2-hydroxyethyl)piperidin-4-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(200 mg) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (4 mL). N,N′-Carbonyldiimidazole (81 mg)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (76 mg) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel chromatography[eluent: methanol/ethyl acetate=5/95→30/70 (volume ratio)] andcrystallized from acetonitrile to give the title compound as colorlesscrystals (51 mg, 23%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.5 Hz, 3H), 1.50-1.68 (m, 4H),2.30-2.40 (m, 2H), 2.58 (br s, 2H), 2.76-2.95 (m, 4H), 3.12-3.15 (m,2H), 3.54-3.58 (m, 2H), 3.95 (s, 2H), 4.40-4.80 (br, 1H), 4.90-5.00 (m,1H), 7.21 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.4 Hz, 2H), 7.41-7.50 (m, 2H),7.57-7.63 (m, 2H), 8.18 (s, 1H), 11.20-12.20 (br, 1H).

Example 3794-[trans-4-(2-hydroxypropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (271 mg), sodium hydrogencarbonate (437 mg) and dimethyl sulfoxide (3 mL) was stirred at 60° C.for 30 min,4′-({4-[trans-4-(2-hydroxypropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(138 mg) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.17 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogensulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gelchromatography [eluent: hexane/ethyl acetate=65/35→35/65 (volume ratio)]to give the title compound as a colorless amorphous compound (57 mg,37%).

¹H NMR (300 MHz, CDCl₃) δ 1.08 (t, J=7.5 Hz, 3H), 1.13 (d, J=6.0 Hz,3H), 1.35-1.47 (m, 2H), 1.72-1.80 (m, 4H), 2.14-2.18 (m, 2H), 2.60-2.72(m, 3H), 3.03-3.08 (m, 2H), 3.20-3.26 (m, 1H), 3.38-3.50 (m, 2H),3.89-3.97 (m, 3H), 4.97-5.05 (m, 1H), 7.25 (d, J=8.4 Hz, 2H), 7.31 (d,J=8.4 Hz, 2H), 7.39-7.41 (m, 1H), 7.45-7.51 (m, 1H), 7.57-7.62 (m, 1H),7.79-7.82 (m, 1H), 7.90 (s, 1H), 8.21 (br s, 1H).

Example 3804-[1-(2-hydroxy-2-methylpropyl)piperidin-4-yl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onetrifluoroacetate

A mixture of hydroxylammonium chloride (646 mg), sodium hydrogencarbonate (1.04 g) and dimethyl sulfoxide (3 mL) was stirred at 60° C.for 30 min,4′-({4-[1-(2-hydroxy-2-methylpropyl)piperidin-4-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(325 mg) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (122 mg)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (114 mg) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by preparative HPLC [eluent: 0.1%trifluoroacetic acid-containing acetonitrile/0.1% trifluoroacetic acidcontaining-water=5/95→100/0 (volume ratio)] to give the title compoundas a colorless amorphous compound (165 mg, 38%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.5 Hz, 3H), 1.27 (s, 6H),1.54-1.57 (m, 2H), 1.88-1.91 (m, 2H), 2.94 (br s, 2H), 3.09-3.77 (m,8H), 3.97 (s, 2H), 5.10-5.25 (m, 2H), 7.21 (d, J=7.5 Hz, 2H), 7.32 (d,J=7.5 Hz, 2H), 7.47-7.57 (m, 2H), 7.63-7.70 (m, 2H), 8.23 (s, 1H),9.16-9.34 (br, 1H), 12.43 (br s, 1H).

Example 3814-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (459 mg), sodium hydrogencarbonate (739 mg) and dimethyl sulfoxide (3 mL) was stirred at 60° C.for 30 min,4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(237 mg) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (86 mg)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (81 mg) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel chromatography[eluent: hexane/ethyl acetate=65/35→35/65 (volume ratio)] to give thetitle compound as a colorless amorphous compound (102 mg, 39%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91 (t, J=7.5 Hz, 3H), 1.05 (s, 6H),1.22-1.34 (m, 2H), 1.49-1.56 (m, 2H), 1.66-1.70 (m, 2H), 2.07-2.11 (m,2H), 2.50-2.62 (m, 2H), 2.89-2.94 (m, 2H), 3.18 (s, 2H), 3.28-3.36 (m,1H), 3.94 (s, 2H), 4.22 (s, 1H), 4.85-4.93 (m, 1H), 7.19 (d, J=8.1 Hz,2H), 7.28 (d, J=8.1 Hz, 2H), 7.46-7.54 (m, 2H), 7.61-7.68 (m, 2H), 8.15(s, 1H), 12.00-12.70 (br, 1H).

Example 3824-[1-(4-hydroxyphenyl)piperidin-4-yl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (344 mg), sodium hydrogencarbonate (554 mg) and dimethyl sulfoxide (3 mL) was stirred at 60° C.for 30 min,4′-({4-[1-(4-hydroxyphenyl)piperidin-4-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(180 mg) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (65 mg)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (61 mg) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel chromatography[eluent: hexane/ethyl acetate=70/30→45/55 (volume ratio)] andcrystallized from a mixture of ethyl acetate and diisopropyl ether togive the title compound as colorless crystals (72 mg, 36%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.2 Hz, 3H), 1.52-1.59 (m, 2H),1.70-1.73 (m, 2H), 2.63-2.70 (m, 2H), 2.80-2.97 (m, 4H), 3.56 (br d,J=12.6 Hz, 2H), 3.97 (s, 2H), 4.97-5.05 (m, 1H), 6.64 (d, J=9.0 Hz, 2H),6.83 (d, J=9.0 Hz, 2H), 7.21 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.4 Hz, 2H),7.48-7.56 (m, 2H), 7.63-7.70 (m, 2H), 8.18 (s, 1H), 8.82 (s, 1H), 12.36(br s, 1H).

Example 3834-[cis-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.20 g), sodium hydrogencarbonate (1.93 g) and dimethyl sulfoxide (5 mL) was stirred at 60° C.for 30 min,4′-({4-[cis-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(620 mg) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (224 mg)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (210 mg) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel chromatography[eluent: hexane/ethyl acetate=65/35→35/65 (volume ratio)] to give thetitle compound as a colorless amorphous compound (479 mg, 70%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.5 Hz, 3H), 1.18 (s, 6H),1.40-1.57 (m, 6H), 1.97-2.02 (m, 2H), 2.78-3.14 (m, 4H), 3.55 (br s,1H), 3.96 (s, 2H), 4.20 (s, 1H), 4.89-4.97 (m, 1H), 7.21 (d, J=8.4 Hz,2H), 7.30 (d, J=8.4 Hz, 2H), 7.48-7.56 (m, 2H), 7.63-7.70 (m, 2H), 8.13(s, 1H), 12.35 (br s, 1H).

Example 3844-[cis-4-(2-hydroxy-2-methylpropoxy)-4-methylcyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (532 mg), sodium hydrogencarbonate (857 mg) and dimethyl sulfoxide (3 mL) was stirred at 60° C.for 30 min,4′-({4-[cis-4-(2-hydroxy-2-methylpropoxy)-4-methylcyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(282 mg) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (101 mg)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (94 mg) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel chromatography[eluent: hexane/ethyl acetate=65/35→35/65 (volume ratio)] andcrystallized from diisopropyl ether to give the title compound ascolorless crystals (166 mg, 53%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.5 Hz, 3H), 1.11 (s, 3H), 1.20(s, 6H), 1.37-1.57 (m, 6H), 1.88 (br d, J=14.4 Hz, 2H), 2.81-2.94 (m,4H), 3.06 (s, 2H), 3.95 (s, 2H), 4.20 (s, 1H), 4.89-4.97 (m, 1H), 7.21(d, J=8.4 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H), 7.47-7.56 (m, 2H), 7.62-7.70(m, 2H), 8.09 (s, 1H), 12.33 (br s, 1H).

Example 3854-[trans-4-(2-hydroxy-2-methylpropoxy)-4-methylcyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (240 mg), sodium hydrogencarbonate (386 mg) and dimethyl sulfoxide (3 mL) was stirred at 60° C.for 30 min,4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)-4-methylcyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(125 mg) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (45 mg)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (43 mg) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel chromatography[eluent: hexane/ethyl acetate=65/35→35/65 (volume ratio)] andcrystallized from diisopropyl ether to give the title compound ascolorless crystals (42 mg, 30%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.2 Hz, 3H), 1.07 (s, 6H), 1.31(s, 3H), 1.50-1.63 (m, 6H), 1.78 (br d, J=12.0 Hz, 2H), 2.54-2.72 (m,2H), 2.90-2.95 (m, 2H), 3.12 (s, 2H), 3.96 (s, 2H), 4.14 (s, 1H),4.89-4.97 (m, 1H), 7.21 (d, J=8.1 Hz, 2H), 7.30 (d, J=8.1 Hz, 2H),7.47-7.56 (m, 2H), 7.62-7.69 (m, 2H), 8.19 (s, 1H), 12.35 (br s, 1H).

Example 3864-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

To a solution of4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(350 mg) in ethanol (2 mL) was added 8M aqueous potassium hydroxidesolution (73 μL), and the mixture was stirred at room temperature for 30min. The solvent was evaporated under reduced pressure to give thecolorless amorphous title compound (320 mg, 86%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.96 (t, J=7.5 Hz, 3H), 1.07 (s, 6H),1.23-1.35 (m, 2H), 1.57-1.72 (m, 4H), 2.08-2.12 (m, 2H), 2.52-2.64 (m,2H), 2.90-2.98 (m, 2H), 3.20 (s, 2H), 3.27-3.33 (m, 1H), 3.91 (s, 2H),4.25 (s, 1H), 4.87-4.95 (m, 1H), 7.17 (d, J=8.4 Hz, 2H), 7.21 (d, J=8.4Hz, 2H), 7.25-7.36 (m, 2H), 7.38-7.48 (m, 2H), 8.16 (s, 1H).

Example 3876-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl-4-(tetrahydro-2H-pyran-4-yl)[1,2,3]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (438 mg), sodium hydrogencarbonate (706 mg) and dimethyl sulfoxide (3 mL) was stirred at 60° C.for 30 min,4′-{[5-oxo-7-propyl-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro[1,2,3]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(192 mg) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (83 mg)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (78 mg) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel chromatography[eluent: hexane/ethyl acetate=70/30→30/70 (volume ratio)] andcrystallized from diisopropyl ether to give the title compound ascolorless crystals (137 mg, 64%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.5 Hz, 3H), 1.55-1.66 (m, 4H),2.40-2.51 (m, 2H), 3.09 (t, J=7.5 Hz, 2H), 3.44-3.51 (m, 2H), 3.99 (brs, 4H), 4.82-4.94 (m, 1H), 7.22 (d, J=8.1 Hz, 2H), 7.32 (d, J=8.1 Hz,2H), 7.48-7.56 (m, 2H), 7.63-7.70 (m, 2H), 7.96 (s, 1H), 12.37 (br s,1H).

Example 3884-[5-hydroxytricyclo[3.3.1.1^(3,7)]dec-2-yl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(less polar isomer)

A mixture of hydroxylammonium chloride (177 mg), sodium hydrogencarbonate (286 mg) and dimethyl sulfoxide (2 mL) was stirred at 60° C.for 30 min, a solution of4′-({4-[(1R,3S,5S,7S)-5-hydroxytricyclo[3.3.1.1^(3,7)]dec-2-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(less polar isomer) (90 mg) in dimethyl sulfoxide (1 mL) was added, andthe mixture was stirred at 90° C. for 16 hr. The reaction mixture wasdiluted with ethyl acetate, washed with water and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was dissolved intetrahydrofuran (8 mL). N,N′-Carbonyldiimidazole (34 mg) and then1,8-diazabicyclo[5.4.0]undec-7-ene (32 mg) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel chromatography[eluent: hexane/ethyl acetate=50/50-÷0/100 (volume ratio)] to give thetitle compound as a colorless amorphous compound (27 mg, 27%).

¹H NMR (300 MHz, CDCl₃) δ 1.10 (t, J=7.5 Hz, 3H), 1.56-1.88 (m, 12H),2.16-2.35 (m, 2H), 2.99-3.10 (m, 4H), 3.93 (s, 2H), 4.61 (br s, 1H),7.27 (d, J=9.0 Hz, 2H), 7.30 (d, J=9.0 Hz, 2H), 7.40-7.48 (m, 2H),7.56-7.62 (m, 1H), 7.71-7.74 (m, 1H), 7.87 (1, 1H), 8.00-9.00 (br, 1H).

Example 3894-[5-hydroxytricyclo[3.3.1.1^(3,7)]dec-2-yl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(highly-polar isomer)

A mixture of hydroxylammonium chloride (198 mg), sodium hydrogencarbonate (319 mg) and dimethyl sulfoxide (2 mL) was stirred at 60° C.for 30 min, a solution of4′-({4-[(1R,3S,5S,7S)-5-hydroxytricyclo[3.3.1.1³′⁷]dec-2-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(highly-polar isomer) (99 mg) in dimethyl sulfoxide (1 mL) was added,and the mixture was stirred at 90° C. for 16 hr. The reaction mixturewas diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was dissolved intetrahydrofuran (8 mL). N,N′-Carbonyldiimidazole (37 mg) and then1,8-diazabicyclo[5.4.0]undec-7-ene (35 mg) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel chromatography[eluent: hexane/ethyl acetate=60/40→35/65 (volume ratio)] to give thetitle compound as a colorless amorphous compound (56 mg, 51%).

¹H NMR (300 MHz, CDCl₃) δ 1.06 (t, J=7.2 Hz, 3H), 1.52 (br d, J=12.9 Hz,2H), 1.68-1.84 (m, 7H), 1.94-1.98 (m, 2H), 2.16-2.25 (m, 3H), 2.92 (brs, 2H), 3.00-3.06 (m, 2H), 3.96 (s, 2H), 4.76 (br s, 1H), 7.24 (d, J=9.0Hz, 2H), 7.28 (d, J=9.0 Hz, 2H), 7.38-7.41 (m, 1H), 7.44-7.50 (m, 1H),7.56-7.62 (m, 1H), 7.77-7.80 (m, 1H), 7.88 (s, 1H), 8.00-9.00 (br, 1H).

Example 3906-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-(7-oxooxepan-4-yl)-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

To a solution of4-(4-oxocyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(262 mg) in acetonitrile (10 mL) was added m-chloroperbenzoic acid (129mg), and the mixture was stirred at room temperature for 15 hr. Thereaction mixture was diluted with ethyl acetate, washed with 5% aqueoussodium thiosulfate solution and then with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gelchromatography [eluent: hexane/ethyl acetate=40/60→0/100 (volume ratio)]and crystallized from a mixture of ethyl acetate and diisopropyl etherto give the title compound as colorless crystals (204 mg, 75%).

¹H NMR (300 MHz, CDCl₃) δ 1.07 (t, J=7.5 Hz, 3H), 1.69-1.81 (m, 2H),1.88-2.02 (m, 2H), 2.67-2.71 (m, 2H), 2.85-3.19 (m, 4H), 3.95 (s, 2H),4.22-4.37 (m, 2H), 5.22-5.30 (m, 1H), 7.22-7.28 (m, 4H), 7.40-7.43 (m,1H), 7.44-7.50 (m, 1H), 7.57-7.62 (m, 1H), 7.71-7.74 (m, 1H), 7.87 (s,1H), 9.00-9.35 (br, 1H).

Example 3914-[(5S,8S)-2-(hydroxymethyl)-1-oxaspiro[4.5]dec-8-yl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (605 mg), sodium hydrogencarbonate (975 mg) and dimethyl sulfoxide (3 mL) was stirred at 60° C.for 30 min, a solution of4′-({4-[(5S,8S)-2-(hydroxymethyl)-1-oxaspiro[4.5]dec-8-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(314 mg) in dimethyl sulfoxide (2 mL) was added, and the mixture wasstirred at 90° C. for 16 hr. The reaction mixture was diluted with ethylacetate, washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was dissolved in tetrahydrofuran (3 mL).N,N′-Carbonyldiimidazole (114 mg) and then1,8-diazabicyclo[5.4.0]undec-7-ene (107 mg) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel chromatography[eluent: hexane/ethyl acetate=40/60→0/100 (volume ratio)] to give thetitle compound as a colorless amorphous compound (27 mg, 8%).

¹H NMR (300 MHz, CDCl₃) δ 1.09 (t, J=7.5 Hz, 3H), 1.43-1.94 (m, 12H),2.77-3.10 (m, 5H), 3.43 (dd, J=11.7, 6.6 Hz, 1H), 3.64 (dd, J=11.4, 3.0Hz, 1H), 3.95 (s, 2H), 4.00-4.10 (m, 1H), 4.87-4.97 (m, 1H), 7.24-7.30(m, 4H), 7.40-7.48 (m, 2H), 7.56-7.61 (m, 1H), 7.76-7.79 (m, 1H), 7.91(s, 1H), 8.00-9.50 (br, 1H).

Example 3924-[(5R,8R)-2-(hydroxymethyl)-1-oxaspiro[4.5]dec-8-yl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (271 mg), sodium hydrogencarbonate (437 mg) and dimethyl sulfoxide (1.5 mL) was stirred at 60° C.for 30 min, a solution of4′-({4-[(5R,8R)-2-(hydroxymethyl)-1-oxaspiro[4.5]dec-8-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(138 mg) in dimethyl sulfoxide (1.5 mL) was added, and the mixture wasstirred at 90° C. for 16 hr. The reaction mixture was diluted with ethylacetate, washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was dissolved in tetrahydrofuran (3 mL).N,N′-Carbonyldiimidazole (52 mg) and then1,8-diazabicyclo[5.4.0]undec-7-ene (49 mg) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel chromatography[eluent: hexane/ethyl acetate=40/60→0/100 (volume ratio)] to give thetitle compound as a colorless amorphous compound (29 mg, 19%).

¹H NMR (300 MHz, CDCl₃) δ 1.07 (t, J=7.5 Hz, 3H), 1.58-1.87 (m, 9H),1.92-2.06 (m, 4H), 2.63-2.74 (m, 2H), 3.01-3.07 (m, 2H), 3.44 (dd,J=11.7, 5.7 Hz, 1H), 3.64 (dd, J=11.7, 3.3 Hz, 1H), 3.96 (s, 2H),4.05-4.12 (m, 1H), 4.97-5.05 (m, 1H), 7.25 (d, J=8.4 Hz, 2H), 7.30 (d,J=8.4 Hz, 2H), 7.40-7.43 (m, 1H), 7.45-7.51 (m, 1H), 7.57-7.63 (m, 1H),7.76-7.79 (m, 1H), 7.90 (s, 1H), 8.20-9.50 (br, 1H).

Example 3934-[(5S,8S)-2-(2-hydroxypropan-2-yl)-1-oxaspiro[4.5]dec-8-yl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (292 mg), sodium hydrogencarbonate (470 mg) and dimethyl sulfoxide (1.5 mL) was stirred at 60° C.for 30 min, a solution of4′-({4-[(5S,8S)-2-(2-hydroxypropan-2-yl)-1-oxaspiro[4.5]dec-8-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(158 mg) in dimethyl sulfoxide (1.5 mL) was added, and the mixture wasstirred at 90° C. for 16 hr. The reaction mixture was diluted with ethylacetate, washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was dissolved in tetrahydrofuran (3 mL).N,N′-Carbonyldiimidazole (55 mg) and then1,8-diazabicyclo[5.4.0]undec-7-ene (52 mg) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel chromatography[eluent: hexane/ethyl acetate=50/50→25/75 (volume ratio)] to give thetitle compound as a colorless amorphous compound (39 mg, 22%).

¹H NMR (300 MHz, CDCl₃) δ 1.08 (t, J=7.5 Hz, 3H), 1.13 (s, 3H), 1.23 (s,3H), 1.44-1.58 (m, 4H), 1.71-1.86 (m, 8H), 2.20-2.80 (br, 1H), 2.84-3.00(m, 2H), 3.04-3.09 (m, 2H), 3.77-3.82 (m, 1H), 3.97 (s, 2H), 4.91-4.99(m, 1H), 7.26 (d, J=9.0 Hz, 2H), 7.29 (d, J=9.0 Hz, 2H), 7.39-7.43 (m,1H), 7.43-7.49 (m, 1H), 7.56-7.61 (m, 1H), 7.78-7.81 (m, 1H), 7.90 (s,1H), 8.50-9.50 (br, 1H).

Example 3944-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,3]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (292 mg), sodium hydrogencarbonate (470 mg) and dimethyl sulfoxide (2 mL) was stirred at 60° C.for 30 min, a solution of4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,3]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(153 mg) in dimethyl sulfoxide (2 mL) was added, and the mixture wasstirred at 90° C. for 18 hr. The reaction mixture was diluted with ethylacetate, washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was dissolved in tetrahydrofuran (3 mL).N,N′-Carbonyldiimidazole (55 mg) and then1,8-diazabicyclo[5.4.0]undec-7-ene (52 mg) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel chromatography[eluent: hexane/ethyl acetate=50/50→30/70 (volume ratio)] to give thetitle compound as a colorless amorphous compound (68 mg, 41%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.2 Hz, 3H), 1.08 (s, 6H),1.28-1.40 (m, 2H), 1.55-1.62 (m, 2H), 1.68-1.71 (m, 2H), 2.08-2.12 (m,2H), 2.20-2.32 (m, 2H), 3.06-3.11 (m, 2H), 3.19 (s, 2H), 3.34-3.50 (m,1H), 3.97 (s, 2H), 4.26 (s, 1H), 4.70 (br s, 1H), 7.22 (d, J=8.1 Hz,2H), 7.31 (d, J=8.1 Hz, 2H), 7.48-7.56 (m, 2H), 7.63-7.70 (m, 2H), 8.02(s, 1H), 12.20-12.60 (br, 1H).

Example 3954-[(5S,8S)-3-hydroxy-1-oxaspiro[4.5]dec-8-yl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (469 mg), sodium hydrogencarbonate (756 mg) and dimethyl sulfoxide (1.5 mL) was stirred at 60° C.for 30 min, a solution of4′-({4-[(5S,8S)-3-hydroxy-1-oxaspiro[4.5]dec-8-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(238 mg) in dimethyl sulfoxide (1.5 mL) was added, and the mixture wasstirred at 90° C. for 20 hr. The reaction mixture was diluted with ethylacetate, washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was dissolved in tetrahydrofuran (3 mL).N,N′-Carbonyldiimidazole (97 mg) and then1,8-diazabicyclo[5.4.0]undec-7-ene (91 mg) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel chromatography[eluent: hexane/ethyl acetate=35/65→0/100 (volume ratio)] to give thetitle compound as a colorless amorphous compound (170 mg, 65%).

¹H NMR (300 MHz, CDCl₃) δ 1.07 (t, J=7.5 Hz, 3H), 1.45-1.64 (m, 4H),1.70-1.82 (m, 4H), 1.91-1.98 (m, 1H), 2.07-2.12 (m, 1H), 2.20-2.50 (br,1H), 2.83-2.97 (m, 2H), 3.02-3.07 (m, 2H), 3.78 (d, J=9.9 Hz, 1H), 3.87(dd, J=9.9, 4.2 Hz, 1H), 3.94 (s, 2H), 4.41-4.44 (m, 1H), 4.90-4.98 (m,1H), 7.24 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.4 Hz, 2H), 7.39-7.47 (m, 2H),7.55-7.60 (m, 1H), 7.72-7.75 (m, 1H), 7.89 (s, 1H), 8.60-9.60 (br, 1H).

Example 3964-[(5R,8R)-3-hydroxy-1-oxaspiro[4.5]dec-8-yl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (208 mg), sodium hydrogencarbonate (336 mg) and dimethyl sulfoxide (1.5 mL) was stirred at 60° C.for 30 min, a solution of4′-({4-[(5R,8R)-3-hydroxy-1-oxaspiro[4.5]dec-8-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(105 mg) in dimethyl sulfoxide (1.5 mL) was added, and the mixture wasstirred at 90° C. for 20 hr. The reaction mixture was diluted with ethylacetate, washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was dissolved in tetrahydrofuran (3 mL).N,N′-Carbonyldiimidazole (39 mg) and then1,8-diazabicyclo[5.4.0]undec-7-ene (37 mg) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel chromatography[eluent: hexane/ethyl acetate=50/50→0/100 (volume ratio)] to give thetitle compound as a colorless amorphous compound (35 mg, 30%).

¹H NMR (300 MHz, CDCl₃) δ 1.11 (t, J=7.5 Hz, 3H), 1.64-1.81 (m, 8H),2.05-2.20 (m, 3H), 2.68-2.77 (m, 2H), 3.03-3.08 (m, 2H), 3.83 (dd,J=9.9, 2.1 Hz, 1H), 3.95 (dd, J=9.9, 3.9 Hz, 1H), 3.98 (s, 2H), 4.54 (brs, 1H), 4.96-5.04 (m, 1H), 7.25 (d, J=8.1 Hz, 2H), 7.31 (d, J=8.1 Hz,2H), 7.39-7.42 (m, 1H), 7.46-7.51 (m, 1H), 7.57-7.63 (m, 1H), 7.82-7.85(m, 1H), 7.92 (s, 1H), 7.94-8.06 (br, 1H).

Example 3974-[(5R,8R)-3-hydroxy-3-methyl-1-oxaspiro[4.5]dec-8-yl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (208 mg), sodium hydrogencarbonate (336 mg) and dimethyl sulfoxide (1.5 mL) was stirred at 60° C.for 30 min, a solution of4′-({4-[(5R,8R)-3-hydroxy-3-methyl-1-oxaspiro[4.5]dec-8-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(109 mg) in dimethyl sulfoxide (1.5 mL) was added, and the mixture wasstirred at 90° C. for 20 hr. The reaction mixture was diluted with ethylacetate, washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was dissolved in tetrahydrofuran (3 mL).N,N′-Carbonyldiimidazole (39 mg) and then1,8-diazabicyclo[5.4.0]undec-7-ene (37 mg) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel chromatography[eluent: hexane/ethyl acetate=40/60→15/85 (volume ratio)] to give thetitle compound as a colorless amorphous compound (30 mg, 25%).

¹H NMR (300 MHz, CDCl₃) δ 1.09 (t, J=7.5 Hz, 3H), 1.42 (s, 3H),1.60-2.08 (m, 10H), 2.27 (d, J=14.8 Hz, 1H), 2.59-2.78 (m, 2H),3.03-3.08 (m, 2H), 3.67 (d, J=9.3 Hz, 1H), 3.77 (d, J=9.3 Hz, 1H), 3.98(s, 2H), 4.99-5.07 (m, 1H), 7.26 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.4 Hz,2H), 7.38-7.41 (m, 1H), 7.46-7.52 (m, 1H), 7.57-7.63 (m, 1H), 7.84-7.87(m, 1H), 7.91 (s, 1H), 8.00-9.00 (br, 1H).

Example 3984-[(5R,8R)-3-ethyl-3-hydroxy-1-oxaspiro[4.5]dec-8-yl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (202 mg), sodium hydrogencarbonate (319 mg) and dimethyl sulfoxide (1.5 mL) was stirred at 60° C.for 30 min, a solution of4′-({4-[(5R,8R)-3-ethyl-3-hydroxy-1-oxaspiro[4.5]dec-8-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(105 mg) in dimethyl sulfoxide (1.5 mL) was added, and the mixture wasstirred at 90° C. for 20 hr. The reaction mixture was diluted with ethylacetate, washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was dissolved in tetrahydrofuran (3 mL).N,N′-Carbonyldiimidazole (39 mg) and then1,8-diazabicyclo[5.4.0]undec-7-ene (37 mg) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel chromatography[eluent: hexane/ethyl acetate=50/50→25/75 (volume ratio)] to give thetitle compound as a colorless amorphous compound (27 mg, 23%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.5 Hz, 3H), 1.07 (t, J=7.2 Hz,3H), 1.60-1.88 (m, 11H), 2.03-2.12 (m, 1H), 2.19 (d, J=13.5 Hz, 1H),2.57-2.75 (m, 2H), 3.02-3.07 (m, 2H), 3.68 (d, J=9.6 Hz, 1H), 3.74 (d,J=9.6 Hz, 1H), 3.96 (s, 2H), 4.96-5.04 (m, 1H), 7.25 (d, J=8.4 Hz, 2H),7.30 (d, J=8.4 Hz, 2H), 7.39-7.42 (m, 1H), 7.45-7.51 (m, 1H), 7.57-7.62(m, 1H), 7.78-7.81 (m, 1H), 7.90 (s, 1H), 8.05-8.80 (br, 1H).

Example 3994-(1,4-dioxaspiro[4.5]dec-8-yl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl-2-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (396 mg), sodium hydrogencarbonate (638 mg) and dimethyl sulfoxide (3 mL) was stirred at 60° C.for 30 min,4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-2-(trifluoromethyl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(220 mg) was added, and the mixture was stirred at 90° C. for 20 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (75 mg)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (70 mg) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel chromatography[eluent: hexane/ethyl acetate=70/30→30/70 (volume ratio)] to give thetitle compound as a colorless amorphous compound (162 mg, 67%).

¹H NMR (300 MHz, CDCl₃) δ 1.07 (t, J=7.2 Hz, 3H), 1.67-1.89 (m, 8H),2.79-2.93 (m, 2H), 3.03-3.08 (m, 2H), 3.91-4.01 (m, 6H), 4.93-5.02 (m,1H), 7.24 (d, J=8.4 Hz, 2H), 7.28 (d, J=8.4 Hz, 2H), 7.39-7.42 (m, 1H),7.44-7.50 (m, 1H), 7.57-7.62 (m, 1H), 7.73-7.76 (m, 1H), 8.40-9.60 (br,1H).

Example 4004-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl-2-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (344 mg), sodium hydrogencarbonate (554 mg) and dimethyl sulfoxide (2 mL) was stirred at 60° C.for 30 min,4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-2-(trifluoromethyl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(200 mg) was added, and the mixture was stirred at 90° C. for 20 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (65 mg)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (61 mg) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel chromatography[eluent: hexane/ethyl acetate=50/50→25/75 (volume ratio)] to give thetitle compound as a colorless amorphous compound (149 mg, 68%).

¹H NMR (300 MHz, CDCl₃) δ 1.07 (t, J=7.5 Hz, 3H), 1.17 (s, 6H),1.34-1.48 (m, 2H), 1.68-1.81 (m, 4H), 2.15-2.18 (m, 2H), 2.30-2.55 (br,1H), 2.57-2.71 (m, 2H), 3.02-3.07 (m, 2H), 3.29 (s, 2H), 3.36-3.46 (m,1H), 3.97 (s, 2H), 4.95-5.04 (m, 1H), 7.24 (d, J=8.4 Hz, 2H), 7.29 (d,J=8.4 Hz, 2H), 7.40-7.42 (m, 1H), 7.45-7.50 (m, 1H), 7.57-7.63 (m, 1H),7.73-7.76 (m, 1H), 8.00-9.50 (br, 1H).

Example 4014-[cis-4-(2-hydroxy-2-methylpropyl)-4-methoxycyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (146 mg), sodium hydrogencarbonate (235 mg) and dimethyl sulfoxide (1 mL) was stirred at 60° C.for 30 min, a solution of4′-({4-[cis-4-(2-hydroxy-2-methylpropyl)-4-methoxycyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(79 mg) in dimethyl sulfoxide (1 mL) was added, and the mixture wasstirred at 90° C. for 15 hr. The reaction mixture was diluted with ethylacetate, washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was dissolved in tetrahydrofuran (2 mL).N,N′-Carbonyldiimidazole (28 mg) and then1,8-diazabicyclo[5.4.0]undec-7-ene (26 mg) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel chromatography[eluent: hexane/ethyl acetate=60/40→40/60 (volume ratio)] to give thetitle compound as a colorless amorphous compound (54 mg, 63%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.2 Hz, 3H), 1.19 (s, 6H),1.39-1.56 (m, 6H), 1.59 (s, 2H), 2.06-2.11 (m, 2H), 2.68-2.80 (m, 2H),2.90-2.96 (m, 2H), 3.10 (s, 3H), 3.95 (s, 2H), 4.08 (s, 1H), 4.82-4.90(m, 1H), 7.21 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H), 7.48-7.56 (m,2H), 7.62-7.69 (m, 2H), 8.18 (s, 1H), 11.80-12.80 (br, 1H).

Example 4024-[cis-4-(3-hydroxy-3-methylbutyl)-4-methoxycyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (723 mg), sodium hydrogencarbonate (1.16 g) and dimethyl sulfoxide (2 mL) was stirred at 60° C.for 30 min, a solution of4′-({4-[cis-4-(3-hydroxy-3-methylbutyl)-4-methoxycyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(390 mg) in dimethyl sulfoxide (2 mL) was added, and the mixture wasstirred at 90° C. for 17 hr. The reaction mixture was diluted with ethylacetate, washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was dissolved in tetrahydrofuran (4 mL).N,N′-Carbonyldiimidazole (135 mg) and then1,8-diazabicyclo[5.4.0]undec-7-ene (126 mg) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel chromatography[eluent: hexane/ethyl acetate=50/50→25/75 (volume ratio)] to give thetitle compound as a colorless amorphous compound (323 mg, 75%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.2 Hz, 3H), 1.08 (s, 6H),1.26-1.58 (m, 10H), 1.88-1.92 (m, 2H), 2.69-2.80 (m, 2H), 2.90-2.96 (m,2H), 3.08 (s, 3H), 3.95 (s, 2H), 4.09 (s, 1H), 4.84-4.92 (m, 1H), 7.21(d, J=8.1 Hz, 2H), 7.30 (d, J=8.1 Hz, 2H), 7.48-7.56 (m, 2H), 7.63-7.70(m, 2H), 8.18 (s, 1H), 12.36 (br s, 1H).

Example 4036-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-3-(2-hydroxy-2-methylpropoxy)cyclobutyl]-2-methyl-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (834 mg), sodium hydrogencarbonate (1.34 g) and dimethyl sulfoxide (2 mL) was stirred at 60° C.for 30 min, a solution of3′-fluoro-4′-({4-[trans-3-(2-hydroxy-2-methylpropoxy)cyclobutyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(437 mg) in dimethyl sulfoxide (3 mL) was added, and the mixture wasstirred at 90° C. for 16 hr. The reaction mixture was diluted with ethylacetate, washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was dissolved in tetrahydrofuran (5 mL).N,N′-Carbonyldiimidazole (156 mg) and then1,8-diazabicyclo[5.4.0]undec-7-ene (146 mg) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel chromatography[eluent: hexane/ethyl acetate=50/50→35/65 (volume ratio)] to give thetitle compound as a colorless amorphous compound (328 mg, 68%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.2 Hz, 3H), 1.11 (s, 6H),1.52-1.60 (m, 2H), 2.24-2.31 (m, 2H), 2.37 (s, 3H), 2.85-2.90 (m, 2H),3.08 (s, 2H), 3.11-3.21 (m, 2H), 3.90 (s, 2H), 4.24-4.28 (m, 1H), 4.33(s, 1H), 5.56-5.67 (m, 1H), 6.96-6.99 (m, 1H), 7.13-7.24 (m, 2H),7.51-7.59 (m, 2H), 7.65-7.71 (m, 2H), 12.45 (br s, 1H).

Example 4046-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[cis-3-(2-hydroxy-2-methylpropoxy)cyclobutyl]-2-methyl-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.16 g), sodium hydrogencarbonate (1.87 g) and dimethyl sulfoxide (2 mL) was stirred at 60° C.for 30 min, a solution of3′-fluoro-4′-({4-[cis-3-(2-hydroxy-2-methylpropoxy)cyclobutyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(606 mg) in dimethyl sulfoxide (3 mL) was added, and the mixture wasstirred at 90° C. for 16 hr. The reaction mixture was diluted with ethylacetate, washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was dissolved in tetrahydrofuran (5 mL).N,N′-Carbonyldiimidazole (216 mg) and then1,8-diazabicyclo[5.4.0]undec-7-ene (202 mg) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel chromatography[eluent: hexane/ethyl acetate=50/50→35/65 (volume ratio)] to give thetitle compound as a colorless amorphous compound (542 mg, 81%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.2 Hz, 3H), 1.09 (s, 6H),1.52-1.60 (m, 2H), 2.36 (s, 3H), 2.51-2.61 (m, 2H), 2.85-2.90 (m, 2H),2.96-3.05 (m, 2H), 3.10 (s, 2H), 3.76-3.85 (m, 1H), 3.99 (s, 2H), 4.30(s, 1H), 4.81-4.91 (m, 1H), 6.96-6.99 (m, 1H), 7.12-7.24 (m, 2H),7.50-7.58 (m, 2H), 7.64-7.70 (m, 2H), 12.47 (br s, 1H).

Example 4056-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[cis-3-(2-hydroxy-1,2-dimethylpropoxy)cyclobutyl]-2-methyl-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (806 mg), sodium hydrogencarbonate (1.29 g) and dimethyl sulfoxide (2 mL) was stirred at 60° C.for 30 min, a solution of3′-fluoro-4′-({4-[cis-3-(2-hydroxy-1,2-dimethylpropoxy)cyclobutyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(430 mg) in dimethyl sulfoxide (2 mL) was added, and the mixture wasstirred at 90° C. for 16 hr. The reaction mixture was diluted with ethylacetate, washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was dissolved in tetrahydrofuran (3 mL).N,N′-Carbonyldiimidazole (150 mg) and then1,8-diazabicyclo[5.4.0]undec-7-ene (141 mg) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel chromatography[eluent: hexane/ethyl acetate=50/50→35/65 (volume ratio)] to give thetitle compound as a colorless amorphous compound (542 mg, 81%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.2 Hz, 3H), 1.02 (s, 3H), 1.03(d, J=6.3 Hz, 3H), 1.12 (s, 3H), 1.52-1.57 (m, 2H), 2.36 (s, 3H),2.54-2.58 (m, 2H), 2.85-2.90 (m, 2H), 2.96-3.08 (m, 2H), 3.14 (q, J=6.3Hz, 1H), 3.85-3.94 (m, 3H), 4.13 (s, 1H), 4.83-4.95 (m, 1H), 6.96-6.99(m, 1H), 7.12-7.16 (m, 1H), 7.21 (t, J=7.8 Hz, 1H), 7.51-7.59 (m, 2H),7.65-7.70 (m, 2H), 12.47 (br s, 1H).

Example 4064-{trans-4-[1-(1-hydroxycyclobutyl)ethoxy]cyclohexyl}-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (2.67 g), sodium hydrogencarbonate (4.30 g) and dimethyl sulfoxide (7 mL) was stirred at 60° C.for 30 min, a solution of4′-[(4-{trans-4-[1-(1-hydroxycyclobutyl)ethoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(1.45 g) in dimethyl sulfoxide (8 mL) was added, and the mixture wasstirred at 90° C. for 18 hr. The reaction mixture was diluted with ethylacetate, washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was dissolved in tetrahydrofuran (10 mL).N,N′-Carbonyldiimidazole (503 mg) and then1,8-diazabicyclo[5.4.0]undec-7-ene (472 mg) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel chromatography[eluent: hexane/ethyl acetate=50/50→35/65 (volume ratio)] to give thetitle compound as a colorless amorphous compound (890 mg, 56%).

¹H NMR (300 MHz, CDCl₃) δ 1.08 (t, J=7.5 Hz, 3H), 1.14 (d, J=6.3 Hz,3H), 1.32-1.59 (m, 3H), 1.70-1.90 (m, 4H), 1.98-2.17 (m, 6H), 2.41 (brs, 2H), 2.59-2.74 (m, 2H), 3.03-3.08 (m, 2H), 3.46-3.58 (m, 2H), 3.97(s, 2H), 4.97-5.05 (m, 1H), 7.25 (d, J=7.8 Hz, 2H), 7.32 (d, J=7.8 Hz,2H), 7.39-7.42 (m, 1H), 7.45-7.51 (m, 1H), 7.57-7.63 (m, 1H), 7.80-7.83(m, 1H), 7.91 (s, 1H), 8.20 (br s, 1H).

Example 4074-{trans-4-[1-(1-hydroxycyclobutyl)ethoxy]cyclohexyl}-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

To a solution of4-{trans-4-[1-(1-hydroxycyclobutyl)ethoxy]cyclohexyl}-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(860 mg) in isopropanol (5 mL) was added 8N aqueous potassium hydroxidesolution (173 μL), and the mixture was stirred at room temperature 10min. The solvent was evaporated under reduced pressure, the obtainedresidue was mixed with diisopropyl ether (15 mL), and the mixture wasstirred at room temperature for 3 hr. The precipitate was collected byfiltration, and dried to give the title compound as a white powder (905mg, 99%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.96 (t, J=7.5 Hz, 3H), 1.01 (d, J=6.9 Hz,3H), 1.17-2.13 (m, 15H), 2.50-2.60 (m, 2H), 2.92-2.97 (m, 2H), 3.31-3.43(m, 2H), 3.90 (s, 2H), 4.85-4.95 (m, 1H), 7.16 (d, J=8.4 Hz, 2H), 7.21(d, J=8.4 Hz, 2H), 7.25-7.47 (m, 4H), 8.16 (s, 1H).

Example 4084-{cis-4-[1-(1-hydroxycyclobutyl)ethoxy]cyclohexyl}-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.92 g), sodium hydrogencarbonate (1.48 g) and dimethyl sulfoxide (3 mL) was stirred at 60° C.for 30 min, a solution of4′-[(4-{cis-4-[1-(1-hydroxycyclobutyl)ethoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.50 g) in dimethyl sulfoxide (4 mL) was added, and the mixture wasstirred at 90° C. for 18 hr. The reaction mixture was diluted with ethylacetate, washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was dissolved in tetrahydrofuran (5 mL).N,N′-Carbonyldiimidazole (178 mg) and then1,8-diazabicyclo[5.4.0]undec-7-ene (167 mg) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel chromatography[eluent: hexane/ethyl acetate=60/40→35/65 (volume ratio)] to give thetitle compound as a colorless amorphous compound (278 mg, 51%).

¹H NMR (300 MHz, CDCl₃) δ 1.08 (t, J=7.5 Hz, 3H), 1.16 (d, J=6.3 Hz,3H), 1.37-1.62 (m, 6H), 1.72-2.21 (m, 8H), 2.76-3.09 (m, 4H), 3.52 (q,J=6.3 Hz, 1H), 3.76 (br s, 1H), 3.76-3.96 (m, 1H), 3.96 (s, 2H),4.98-5.06 (m, 1H), 7.26 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H),7.41-7.49 (m, 2H), 7.56-7.62 (m, 1H), 7.79-7.81 (m, 1H), 7.91 (s, 1H),8.20-9.60 (br, 1H).

Example 4094-[4-(2-hydroxy-1,1,2-trimethylpropoxy)phenyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.5 g), sodium hydrogencarbonate (2.2 g) and dimethyl sulfoxide (9 mL) was stirred at 50° C.for 30 min,4′-({4-[4-(2-hydroxy-1,1,2-trimethylpropoxy)phenyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.98 g) was added, and the mixture was stirred at 90° C. for 15 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (9 mL). N,N′-Carbonyldiimidazole (0.34 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.31 mL) were added, andthe mixture was stirred at room temperature for 1 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid, saturated aqueous sodium hydrogen carbonate solution and saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as apale-yellow amorphous solid (0.52 g, 48%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.97 (t, J=7.4 Hz, 3H), 1.26 (s, 12 H),1.53-1.68 (m, 2H), 2.96-3.03 (m, 2H), 4.00 (s, 2H), 4.44 (s, 1H),7.07-7.76 (m, 12H), 8.07 (s, 1H), 12.39 (s, 1H)

Example 4104-[4-(2-hydroxy-1,1-dimethylpropoxy)phenyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (1.1 g), sodium hydrogencarbonate (1.6 g) and dimethyl sulfoxide (6 mL) was stirred at 50° C.for 30 min,4′-({4-[4-(2-hydroxy-1,1-dimethylpropoxy)phenyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.70 g) was added, and the mixture was stirred at 90° C. for 15 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (6 mL). N,N′-Carbonyldiimidazole (0.25 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added, andthe mixture was stirred at room temperature for 1 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated aqueous sodium hydrogen carbonate solutionand saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas a pale-yellow amorphous solid (0.34, 43%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.14 (t, J=7.4 Hz, 3H), 1.21 (d, J=6.4Hz, 3H), 1.27 (s, 6H), 1.77-1.92 (m, 2H), 2.57-2.68 (m, 1H), 3.09-3.23(m, 2H), 3.86 (q, J=6.4 Hz, 1H), 4.02 (s, 2H), 7.04-8.38 (m, 14H)

Example 4114-[4-(1,1-dimethyl-2-oxopropoxy)phenyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

To a solution of4-[4-(2-hydroxy-1,1-dimethylpropoxy)phenyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(0.24 g) in methylene chloride (4 mL) was added1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (0.25 g),and the mixture was stirred for 3 hr. Ethyl acetate, water and sodiumthiosulfate were added to the reaction mixture, and the mixture wasstirred for 30 min. After stirring, the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas purified by silica gel column chromatography to give the titlecompound as a colorless amorphous solid (0.20 g, 85%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.97 (t, J=7.3 Hz, 3H), 1.49 (s, 6H),1.53-1.68 (m, 2H), 2.28 (s, 3H), 2.94-3.03 (m, 2H), 3.99 (s, 2H),6.83-7.74 (m, 12H), 8.06 (s, 1H), 12.39 (s, 1H)

Example 4124-(trans-4-hydroxycyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.70 g), sodium hydrogencarbonate (1.0 g) and dimethyl sulfoxide (5 mL) was stirred at 50° C.for 30 min,4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.47 g) was added, and the mixture was stirred at 90° C. for 23 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.20 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.18 mL) were added, andthe mixture was stirred at room temperature for 1 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid, then saturated aqueous sodium hydrogen carbonate solution andsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.48 g, 90%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H), 1.27-1.98 (m, 6H),2.19-2.53 (m, 4H), 2.89-3.02 (m, 2H), 3.49-3.65 (m, 1H), 3.93 (s, 2H),4.53-4.92 (m, 2H), 6.40 (d, J=2.1 Hz, 1H), 7.15-7.87 (m, 9H), 12.36 (s,1H)

Example 4134-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (42 g), sodium hydrogen carbonate(61 g) and dimethyl sulfoxide (240 mL) was stirred at 50° C. for 30 min.4′-({4-[trans-4-(2-Hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(32 g) was added, and the mixture was stirred at 90° C. for 15 hr. Themixture was allowed to cool to room temperature, and the reactionmixture was diluted with ethyl acetate and water. After extraction withethyl acetate, the organic layer was washed with brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was dissolved in tetrahydrofuran (300 mL).N,N′-Carbonyldiimidazole (11.5 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene(10.6 mL) were successively added to the tetrahydrofuran solutionmentioned above, and the mixture was stirred at room temperature for 2hr. The reaction mixture was diluted with ethyl acetate, and 1 Mhydrochloric acid was added. After extraction with ethyl acetate, theorganic layer was successively washed with saturated aqueous sodiumhydrogen carbonate and brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography to give thetitle compound as an amorphous solid. The solid was dissolved inacetone, and crystallized. The resulting solid was collected byfiltration, washed with acetone, and dried under reduced pressure togive the title compound as a colorless solid (25.9 g, 73%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.4 Hz, 3H), 1.07 (s, 6H),1.25-1.76 (m, 6H), 2.02-2.48 (m, 4H), 2.89-3.00 (m, 2H), 3.20 (s, 2H),3.33-3.46 (m, 1H), 3.93 (s, 2H), 4.24 (s, 1H), 4.67 (br. s., 1H), 6.41(d, J=2.3 Hz, 1H), 7.17-7.85 (m, 9H), 12.35 (br. s., 1H)

Crystal form was characterized by powder X ray diffraction pattern usingCuKα X-ray radiation, having peaks selected from a list consisting of:

diffraction angle: 2θ (°) interplanar distance: d value (Å) 9.94 8.891215.08 5.8702 15.7 5.6398 15.82 5.5973 18.6 4.7665 18.66 4.7513 19.524.5439 19.96 4.4447 23.08 3.8504

Example 4144-(4-oxocyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one

To a solution of4-(trans-4-hydroxycyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one(0.20 g) in methylene chloride (4 mL) was added1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (0.24 g),and the mixture was stirred for 18 hr. Ethyl acetate, water and sodiumthiosulfate were added to the reaction mixture, and the mixture wasstirred for 30 min. After stirring, the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas purified by silica gel column chromatography to give the titlecompound as a colorless amorphous solid (0.091 g, 45%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.2 Hz, 3H), 1.44-1.59 (m, 2H),1.88-2.05 (m, 2H), 2.23-2.39 (m, 2H), 2.57-3.04 (m, 6H), 3.95 (s, 2H),5.18 (br. s., 1H), 6.51 (d, J=2.3 Hz, 1H), 7.15-7.88 (m, 9H), 12.35 (s,1H)

Example 4154-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

To a solution (2 mL) of4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one(0.16 g) in ethanol was added 8M aqueous potassium hydroxide solution(0.034 mL), and the mixture was stirred at room temperature for 1 hr.The reaction mixture was concentrated under reduced pressure, and theresidue was solidified with diisopropyl ether to give the title compoundas a colorless amorphous solid (0.16 g, 94%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.4 Hz, 3H), 1.07 (s, 6H),1.25-1.44 (m, 2H), 1.49-1.74 (m, 4H), 2.03-2.14 (m, 2H), 2.29-2.47 (m,2H), 2.91-3.01 (m, 2H), 3.20 (s, 2H), 3.35-3.48 (m, 1H), 3.88 (s, 2H),4.25 (br. s., 1H), 4.50-4.85 (m, 1H), 6.40 (d, J=2.3 Hz, 1H), 7.11-7.50(m, 8H), 7.81 (d, J=2.3 Hz, 1H)

Example 4164-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-7-propyl-6-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}pyrazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.15 g), trimethylsilylazide (0.54 mL), dibutyltinoxide (0.086 g) andtoluene (3 mL) was stirred at 100° C. for 5 days. Ethyl acetate andwater were added to the reaction mixture, and the mixture was extractedwith ethyl acetate. The organic layer was washed with water and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (2 mL).

Tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 0.9 mL) wasadded, and the mixture was stirred at room temperature for 15 hr. Thereaction mixture was diluted with ethyl acetate, washed with 1 Mhydrochloric acid, then with saturated aqueous sodium hydrogen carbonatesolution and saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless amorphous solid (0.075 g, 45%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.08 (t, J=7.3 Hz, 3H), 1.20 (s, 6H),1.34-1.90 (m, 6H), 2.12-2.53 (m, 4H), 3.05-3.13 (m, 2H), 3.26-3.52 (m,4H), 3.98 (s, 2H), 4.46-4.92 (m, 1H), 6.00 (d, J=2.1 Hz, 1H), 7.13-8.29(m, 9H), 12.06 (s, 1H)

Example 4174-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.68 g), sodium hydrogencarbonate (1.0 g) and dimethyl sulfoxide (5 mL) was stirred at 50° C.for 30 min,4′-({4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.45 g) was added, and the mixture was stirred at 90° C. for 20 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.16 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and with saturated aqueous sodium hydrogen carbonate solution andsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as apale-yellow amorphous solid (0.37 g, 73%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H), 1.00 (s, 3H), 1.05(d, J=6.2 Hz, 3H), 1.09 (s, 3H), 1.23-1.72 (m, 6H), 1.92-2.14 (m, 2H),2.27-2.48 (m, 2H), 2.89-2.99 (m, 2H), 3.24 (q, J=6.2 Hz, 1H), 3.39-3.54(m, 1H), 3.93 (s, 2H), 4.06 (s, 1H), 4.67 (br. s., 1H), 6.43 (d, J=2.1Hz, 1H), 7.15-7.89 (m, 9H), 12.36 (br. s., 1H)

Example 4184-[trans-4-(2-hydroxybutoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one

To a solution of4′-({4-[trans-4-(2-hydroxyethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.64 g) in methylene chloride (6 mL) was added1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (1.1 g),and the mixture was stirred for 5 hr. Ethyl acetate, water and sodiumthiosulfate were added to the reaction mixture, and the mixture wasstirred for 30 min. After stirring, the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate, and the solvent was evaporated. This wasdissolved in tetrahydrofuran (4 mL), ethylmagnesium bromide was addeddropwise (3 M tetrahydrofuran solution, 0.26 mL) at 0° C., and themixture was stirred for 4 hr. The mixture was diluted with ethyl acetateand then saturated aqueous ammonium chloride solution were added. Themixture was extracted with ethyl acetate, and the organic layer waswashed with saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was crudely purified by silica gel columnchromatography. This was dissolved in dimethyl sulfoxide (1.1 mL),hydroxylammonium chloride (0.12 g) and sodium hydrogen carbonate (0.19g) was added, and the mixture was stirred at 90° C. for 20 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (1.1 mL). N,N′-Carbonyldiimidazole (0.027g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.025 mL) were added,and the mixture was stirred at room temperature for 1 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid, then with saturated aqueous sodium hydrogen carbonate solution andsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as apale-yellow amorphous solid (0.046 g, 6%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83-0.97 (m, 6H), 1.20-1.75 (m, 8H),2.02-2.15 (m, 2H), 2.26-2.48 (m, 2H), 2.83-2.99 (m, 2H), 3.22-3.50 (m,4H), 3.93 (s, 2H), 4.40-4.85 (m, 2H), 6.41 (d, J=1.9 Hz, 1H), 7.16-7.89(m, 9H), 12.35 (br. s., 1H)

Example 4194-[trans-4-(2-hydroxypropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.91 g), sodium hydrogencarbonate (1.38 g) and dimethyl sulfoxide (5 mL) was stirred at 50° C.for 30 min,4′-({4-[trans-4-(2-hydroxypropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.57 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.21 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.20 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid, then with saturated aqueous sodium hydrogen carbonate solution andsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.48 g, 76%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.2 Hz, 3H), 1.04 (d, J=6.1 Hz,3H), 1.24-1.75 (m, 6H), 2.02-2.16 (m, 2H), 2.28-2.47 (m, 2H), 2.90-2.98(m, 2H), 3.17-3.26 (m, 1H), 3.29-3.47 (m, 2H), 3.60-3.78 (m, 1H), 3.93(s, 2H), 4.51 (d, J=4.5 Hz, 1H), 4.66 (br. s., 1H), 6.41 (d, J=1.9 Hz,1H), 7.17-7.88 (m, 9H), 12.36 (s, 1H)

Example 4206-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-oxopropoxy)cyclohexyl]-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one

To a solution of4-[trans-4-(2-hydroxypropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one(0.38 g) in methylene chloride (3 mL) was added1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (0.55 g),and the mixture was stirred for 15 hr. Ethyl acetate, water and sodiumthiosulfate were added to the reaction mixture, and the mixture wasstirred for 30 min. After stirring, the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas purified by silica gel column chromatography to give the titlecompound as a colorless amorphous solid (0.34 g, 90%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.2 Hz, 3H), 1.28-1.76 (m, 6H),2.02-2.17 (m, 5H), 2.29-2.48 (m, 2H), 2.88-3.01 (m, 2H), 3.44 (t, J=11.0Hz, 1H), 3.93 (s, 2H), 4.14 (s, 2H), 4.65 (br. s., 1H), 6.41 (d, J=2.3Hz, 1H), 7.19-7.88 (m, 9H), 12.36 (s, 1H)

Example 4214-[trans-4-(2-cyclopropyl-2-hydroxyethoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.68 g), sodium hydrogencarbonate (1.0 g) and dimethyl sulfoxide (4 mL) was stirred at 50° C.for 30 min,4′-({4-[trans-4-(2-cyclopropyl-2-hydroxyethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.45 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (4 mL). N,N′-Carbonyldiimidazole (0.16 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid, then with saturated aqueous sodium hydrogen carbonate solution andsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as apale-yellow amorphous solid (0.40 g, 81%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.17-0.42 (m, 4H), 0.74-0.88 (m, 1H), 0.92(t, J=7.3 Hz, 3H), 1.25-1.74 (m, 6H), 2.05-2.17 (m, 2H), 2.28-2.47 (m,2H), 2.87-3.13 (m, 3H), 3.35-3.49 (m, 3H), 3.93 (s, 2H), 4.50 (d, J=4.9Hz, 1H), 4.69 (br. s., 1H), 6.42 (d, J=2.1 Hz, 1H), 7.18-7.86 (m, 9H),12.38 (s, 1H)

Example 4224-[trans-4-(2-hydroxy-3-methylbutoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.47 g), sodium hydrogencarbonate (0.71 g) and dimethyl sulfoxide (3 mL) was stirred at 50° C.for 30 min,4′-({4-[trans-4-(2-hydroxy-3-methylbutoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.31 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (0.11 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.10 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid, then with saturated aqueous sodium hydrogen carbonate solution andsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.29 g, 85%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (d, J=6.8 Hz, 3H), 0.87 (d, J=7.0 Hz,3H), 0.92 (t, J=7.3 Hz, 3H), 1.24-1.73 (m, 7H), 2.03-2.17 (m, 2H),2.25-2.48 (m, 2H), 2.86-2.99 (m, 2H), 3.26-3.46 (m, 3H), 3.93 (s, 2H),4.41 (d, J=4.5 Hz, 1H), 4.68 (br. s., 1H), 6.42 (d, J=2.1 Hz, 1H),7.17-7.90 (m, 9H), 12.38 (br. s., 1H)

Example 4234-[trans-4-(2-cyclopropyl-2-oxoethoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one

To a solution of4-[trans-4-(2-cyclopropyl-2-hydroxyethoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one(0.25 g) in methylene chloride (3 mL) was added1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (0.35 g),and the mixture was stirred for 2 hr. Ethyl acetate, water and sodiumthiosulfate were added to the reaction mixture, and the mixture wasstirred for 30 min. After stirring, the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas purified by silica gel column chromatography to give the titlecompound as a colorless amorphous solid (0.21 g, 83%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.81-0.99 (m, 7H), 1.31-1.76 (m, 6H),2.05-2.48 (m, 5H), 2.87-3.00 (m, 2H), 3.39-3.53 (m, 1H), 3.93 (s, 2H),4.29 (s, 2H), 4.68 (br. s., 1H), 6.43 (d, J=2.3 Hz, 1H), 7.18-7.86 (m,9H), 12.39 (br. s., 1H)

Example 4244-[trans-4-(3-methyl-2-oxobutoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one

To a solution of4-[trans-4-(2-hydroxy-3-methylbutoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one(0.19 g) in methylene chloride (2 mL) was added1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (0.26 g),and the mixture was stirred for 2 hr. Ethyl acetate, water and sodiumthiosulfate were added to the reaction mixture, and the mixture wasstirred for 30 min. After stirring, the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas purified by silica gel column chromatography to give the titlecompound as a colorless amorphous solid (0.047 g, 25%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H), 1.01 (d, J=6.8 Hz,6H), 1.30-1.75 (m, 6H), 2.04-2.47 (m, 4H), 2.73 (spt, J=6.9 Hz, 1H),2.89-2.99 (m, 2H), 3.38-3.48 (m, 1H), 3.93 (s, 2H), 4.26 (s, 2H), 4.67(br. s., 1H), 6.42 (d, J=2.1 Hz, 1H), 7.06-7.93 (m, 9H), 12.38 (br. s.,1H)

Example 4254-(trans-4-{[(1R,2S)-2-hydroxy-2-methylcyclopropyl]oxy}cyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.56 g), sodium hydrogencarbonate (0.84 g) and dimethyl sulfoxide (3.5 mL) was stirred at 50° C.for 30 min,4′-({4-[trans-4-({2-methyl-2-[(triethylsilyl)oxy]cyclopropyl]oxy)cyclohexyl}-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.44 g) was added, and the mixture was stirred at 90° C. for 20 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (0.13 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.12 mL) were added, andthe mixture was stirred at room temperature for 1 hr. To the reactionmixture was added tetrabutylammonium fluoride (1 M tetrahydrofuransolution, 1.5 mL), and the mixture was stirred at 60° C. for 2 hr. Thereaction mixture was diluted with ethyl acetate, washed with 1 Mhydrochloric acid, then with saturated aqueous sodium hydrogen carbonatesolution and saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography to give thetitle compound as a pale-yellow amorphous solid (0.11 g, 28%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.55 (d, J=5.7 Hz, 2H), 0.93 (t, J=7.3 Hz,3H), 1.20 (s, 3H), 1.30-1.76 (m, 6H), 2.08-2.22 (m, 2H), 2.29-2.48 (m,2H), 2.89-3.03 (m, 3H), 3.48-3.64 (m, 1H), 3.94 (s, 2H), 4.68 (br. s.,1H), 4.88 (s, 1H), 6.43 (d, J=2.1 Hz, 1H), 7.18-7.88 (m, 9H), 12.39 (br.s., 1H)

Example 4264-(trans-4-{[(1R,2R)-2-hydroxy-2-methylcyclopropyl]oxy}cyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.56 g), sodium hydrogencarbonate (0.84 g) and dimethyl sulfoxide (3.5 mL) was stirred at 50° C.for 30 min,4′-({4-[trans-4-({2-methyl-2-[(triethylsilyl)oxy]cyclopropyl}oxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.44 g) was added, and the mixture was stirred at 90° C. for 20 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (0.13 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.12 mL) were added, andthe mixture was stirred at room temperature for 1 hr. To the reactionmixture was added tetrabutylammonium fluoride (1 M tetrahydrofuransolution, 1.5 mL), and the mixture was stirred at 60° C. for 2 hr. Thereaction mixture was diluted with ethyl acetate, washed with 1 Mhydrochloric acid and then with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a pale-yellow amorphous solid (0.82 g, 20%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H), 1.18 (d, J=6.8 Hz,2H), 1.28-1.73 (m, 6H), 2.01-2.19 (m, 5H), 2.26-2.48 (m, 2H), 2.91-3.01(m, 2H), 3.37-3.55 (m, 2H), 3.93 (s, 2H), 3.98-4.07 (m, 1H), 4.72 (br.s., 1H), 6.44 (d, J=2.3 Hz, 1H), 7.17-7.87 (m, 9H), 12.40 (br. s., 1H)

Example 4274-{trans-4-[(1-hydroxycyclopropyl)methoxy]cyclohexyl}-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.83 g), sodium hydrogencarbonate (1.26 g) and dimethyl sulfoxide (5 mL) was stirred at 50° C.for 30 min,4′-[(4-{trans-4-[(1-{[tert-butyl(dimethyl)silyl]oxy}cyclopropyl)methoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.67 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.20 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.18 mL) were added, andthe mixture was stirred at room temperature for 1 hr. To the reactionmixture was added tetrabutylammonium fluoride (1 M tetrahydrofuransolution, 5 mL), and the mixture was stirred at 60° C. for 2 hr. Thereaction mixture was diluted with ethyl acetate, washed with 1 Mhydrochloric acid, then with saturated aqueous sodium hydrogen carbonatesolution and saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography to give thetitle compound as a pale-yellow amorphous solid (0.27 g, 44%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.40-0.59 (m, 4H), 0.92 (t, J=7.2 Hz, 3H),1.25-1.75 (m, 6H), 2.02-2.47 (m, 4H), 2.90-3.01 (m, 2H), 3.36-3.53 (m,3H), 3.93 (s, 2H), 4.49-4.80 (m, 1H), 5.26 (s, 1H), 6.41 (d, J=2.3 Hz,1H), 7.17-7.86 (m, 9H), 12.35 (s, 1H)

Example 4286-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl-4-[trans-4-(3,3,3-trifluoro-2-hydroxypropoxy)cyclohexyl]pyrazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.97 g), sodium hydrogencarbonate (1.46 g) and dimethyl sulfoxide (6 mL) was stirred at 50° C.for 30 min,4′-({5-oxo-7-propyl-4-[trans-4-(3,3,3-trifluoro-2-hydroxypropoxy)cyclohexyl]-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.67 g) was added, and the mixture was stirred at 90° C. for 20 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (6 mL). N,N′-Carbonyldiimidazole (0.23 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.21 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid, then with saturated aqueous sodium hydrogen carbonate solution andsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.53 g, 72%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.4 Hz, 3H), 1.25-1.75 (m, 6H),2.04-2.17 (m, 2H), 2.31-2.47 (m, 2H), 2.88-3.01 (m, 2H), 3.41-3.70 (m,3H), 3.93 (s, 2H), 4.03-4.18 (m, 1H), 4.54-4.83 (m, 1H), 6.33 (d, J=6.4Hz, 1H), 6.41 (d, J=2.3 Hz, 1H), 7.18-7.85 (m, 9H), 12.35 (s, 1H)

Example 429trans-4-[5-oxo-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl]cyclohexyl2-(acetyloxy)-2-methylpropanoate

A mixture of hydroxylammonium chloride (0.66 g), sodium hydrogencarbonate (1.0 g) and dimethyl sulfoxide (4 mL) was stirred at 50° C.for 30 min,trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl2-(acetyloxy)-2-methylpropanoate (0.67 g) was added, and the mixture wasstirred at 90° C. for 20 hr. The reaction mixture was diluted with ethylacetate, washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was dissolved in tetrahydrofuran (4 mL).N,N′-Carbonyldiimidazole (0.15 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid, then withsaturated aqueous sodium hydrogen carbonate solution and saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.28 g, 55%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.4 Hz, 3H), 1.41-1.77 (m, 12H),1.92-2.04 (m, 5H), 2.37-2.57 (m, 2H), 2.88-3.00 (m, 2H), 3.94 (s, 2H),4.59-4.92 (m, 2H), 6.52 (d, J=1.9 Hz, 1H), 7.17-7.88 (m, 9H), 12.40 (s,1H)

Example 430trans-4-[5-oxo-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl]cyclohexyl2-hydroxy-2-methylpropanoate

A mixture of hydroxylammonium chloride (0.66 g), sodium hydrogencarbonate (1.0 g) and dimethyl sulfoxide (4 mL) was stirred at 50° C.for 30 min,trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl2-(acetyloxy)-2-methylpropanoate (0.67 g) was added, and the mixture wasstirred at 90° C. for 20 hr. The reaction mixture was diluted with ethylacetate, washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was dissolved in tetrahydrofuran (4 mL).N,N′-Carbonyldiimidazole (0.15 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid, then withsaturated aqueous sodium hydrogen carbonate solution and saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.083 g, 17%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.2 Hz, 3H), 1.29 (s, 6H),1.43-1.78 (m, 6H), 1.97-2.07 (m, 2H), 2.39-2.57 (m, 2H), 2.90-3.01 (m,2H), 3.94 (s, 2H), 4.55-4.95 (m, 2H), 5.23 (s, 1H), 6.52 (d, J=2.3 Hz,1H), 7.16-7.88 (m, 9H), 12.36 (s, 1H)

Example 4316-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl-4-[trans-4-(3,3,3-trifluoro-2-oxopropoxy)cyclohexyl]pyrazolo[1,5-a]pyrimidin-5(4H)-one

To a solution of6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl-4-[trans-4-(3,3,3-trifluoro-2-hydroxypropoxy)cyclohexyl]pyrazolo[1,5-a]pyrimidin-5(4H)-one(0.14 g) in methylene chloride (2 mL) was added1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (0.14 g),and the mixture was stirred for 3 hr. Ethyl acetate, water and sodiumthiosulfate were added to the reaction mixture, and the mixture wasstirred for 30 min. After stirring, the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas purified by silica gel column chromatography to give the titlecompound as a colorless amorphous solid (0.098 g, 73%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.4 Hz, 3H), 1.27-1.79 (m, 6H),2.03-2.49 (m, 4H), 2.90-3.00 (m, 2H), 3.41-3.54 (m, 1H), 3.94 (s, 2H),4.48-4.85 (m, 1H), 6.41 (d, J=2.3 Hz, 1H), 6.88 (s, 2H), 7.18-7.87 (m,9H), 12.36 (s, 1H)

Example 4324-[trans-4-(2-cyclopropyl-2-hydroxypropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.33 g), sodium hydrogencarbonate (0.49 g) and dimethyl sulfoxide (2 mL) was stirred at 50° C.for 30 min,4′-({4-[trans-4-(2-cyclopropyl-2-hydroxypropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.22 g) was added, and the mixture was stirred at 90° C. for 20 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.076 g)and then with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.070 mL) was added,and the mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid, then with saturated aqueous sodium hydrogen carbonate solution andsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.13 g, 52%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.10-0.40 (m, 4H), 0.82-0.98 (m, 4H), 1.08(s, 3H), 1.26-1.76 (m, 6H), 2.01-2.47 (m, 4H), 2.87-3.01 (m, 2H),3.21-3.49 (m, 3H), 3.86-3.97 (m, 3H), 4.47-4.91 (m, 1H), 6.41 (s, 1H),7.13-7.89 (m, 9H), 12.34 (br. s., 1H)

Example 4334-{trans-4-[(1-hydroxycyclopropyl)methoxy]cyclohexyl}-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

To a solution (2 mL) of4-{trans-4-[(1-hydroxycyclopropyl)methoxy]cyclohexyl}-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one(0.21 g) in ethanol was added 8M aqueous potassium hydroxide solution(0.043 mL), and the mixture was stirred at room temperature for 1 hr.The reaction mixture was concentrated under reduced pressure, and theresidue was solidified with diisopropyl ether to give the title compoundas a colorless amorphous solid (0.20 g, 89%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.42-0.59 (m, 4H), 0.95 (t, J=7.3 Hz, 3H),1.23-1.73 (m, 6H), 2.04-2.47 (m, 4H), 2.90-3.00 (m, 2H), 3.36-3.53 (m,3H), 3.88 (s, 2H), 4.54-4.84 (m, 1H), 5.26 (s, 1H), 6.38 (d, J=2.1 Hz,1H), 7.11-7.51 (m, 8H), 7.81 (d, J=2.1 Hz, 1H)

Example 4347-butyl-4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.49 g), sodium hydrogencarbonate (0.74 g) and dimethyl sulfoxide (3 mL) was stirred at 50° C.for 30 min,4′-({7-butyl-4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.31 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (0.12 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid, then with saturated aqueous sodium hydrogen carbonate solution andsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.27 g, 75%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.79-0.89 (m, 3H), 1.07 (s, 6H), 1.26-1.53(m, 6H), 1.62-1.72 (m, 2H), 2.02-2.15 (m, 2H), 2.29-2.46 (m, 2H),2.92-3.02 (m, 2H), 3.20 (s, 2H), 3.34-3.46 (m, 1H), 3.93 (s, 2H), 4.25(s, 1H), 4.67 (br. s., 1H), 6.42 (d, J=2.3 Hz, 1H), 7.17-7.87 (m, 9H),12.38 (s, 1H)

Example 4356-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.39 g), sodium hydrogencarbonate (0.59 g) and dimethyl sulfoxide (2.5 mL) was stirred at 50° C.for 30 min,3′-fluoro-4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.22 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (0.091 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.084 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid, then with saturated aqueous sodium hydrogen carbonate solution andsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.23 g, 78%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.4 Hz, 3H), 1.07 (s, 6H),1.26-1.73 (m, 6H), 2.03-2.14 (m, 2H), 2.24-2.46 (m, 2H), 2.90-2.99 (m,2H), 3.19 (s, 2H), 3.34-3.45 (m, 1H), 3.92 (s, 2H), 4.24 (s, 1H), 4.64(br. s., 1H), 6.43 (d, J=2.3 Hz, 1H), 6.93-7.86 (m, 8H), 12.44 (s, 1H)

Example 4367-butyl-4-[trans-4-(2-hydroxypropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.43 g), sodium hydrogencarbonate (0.66 g) and dimethyl sulfoxide (3 mL) was stirred at 50° C.for 30 min,4′-({7-butyl-4-[trans-4-(2-hydroxypropoxy)cyclohexyl]-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.27 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (0.10 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.090 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid, then with saturated aqueous sodium hydrogen carbonate solution andsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.22 g, 70%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.80-0.88 (m, 3H), 1.04 (d, J=6.4 Hz, 3H),1.25-1.52 (m, 6H), 1.60-1.74 (m, 2H), 2.03-2.16 (m, 2H), 2.28-2.47 (m,2H), 2.90-3.02 (m, 2H), 3.17-3.25 (m, 1H), 3.30-3.47 (m, 2H), 3.62-3.76(m, 1H), 3.93 (s, 2H), 4.48-4.82 (m, 2H), 6.42 (d, J=1.9 Hz, 1H),7.17-7.86 (m, 9H), 12.38 (s, 1H)

Example 4376-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxypropoxy)cyclohexyl]-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.43 g), sodium hydrogencarbonate (0.66 g) and dimethyl sulfoxide (3 mL) was stirred at 50° C.for 30 min,3′-fluoro-4′-({4-[trans-4-(2-hydroxypropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.27 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (0.10 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.090 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated aqueous sodium hydrogen carbonate solutionand saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless amorphous solid (0.21 g, 68%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.4 Hz, 3H), 1.03 (d, J=6.1 Hz,3H), 1.25-1.74 (m, 6H), 2.02-2.46 (m, 4H), 2.90-3.00 (m, 2H), 3.17-3.45(m, 3H), 3.62-3.76 (m, 1H), 3.92 (s, 2H), 4.46-4.85 (m, 2H), 6.43 (d,J=2.3 Hz, 1H), 6.95-7.89 (m, 8H), 12.44 (s, 1H)

Example 4387-butyl-4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-6-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}pyrazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4′-({7-butyl-4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.27 g), trimethylsilylazide (0.66 mL), dibutyltinoxide (0.060 g) andtoluene (3 mL) was stirred at 100° C. for 20 hr. Ethyl acetate and waterwere added to the reaction mixture, and the mixture was extracted withethyl acetate. The organic layer was washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was dissolved intetrahydrofuran (3 mL). Tetrabutylammonium fluoride (1.0 Mtetrahydrofuran solution, 0.75 mL) was added, and the mixture wasstirred at room temperature for 3 hr. The reaction mixture was dilutedwith ethyl acetate, washed with 1 M hydrochloric acid, then withsaturated aqueous sodium hydrogen carbonate solution and saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.13 g, 46%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.77-0.86 (m, 3H), 1.07 (s, 6H), 1.26-1.73(m, 8H), 2.03-2.46 (m, 4H), 2.87-2.97 (m, 2H), 3.20 (s, 2H), 3.35-3.46(m, 1H), 3.87 (s, 2H), 4.24 (s, 1H), 4.67 (br. s., 1H), 6.40 (d, J=2.1Hz, 1H), 6.94-7.86 (m, 10H)

Example 4396-{[3-fluoro-2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of3′-fluoro-4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.26 g), trimethylsilylazide (0.66 mL), dibutyltinoxide (0.060 g) andtoluene (3 mL) was stirred at 100° C. for 20 hr. Ethyl acetate and waterwere added to the reaction mixture, and the mixture was extracted withethyl acetate. The organic layer was washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was dissolved intetrahydrofuran (3 mL). Tetrabutylammonium fluoride (1.0 Mtetrahydrofuran solution, 0.9 mL) was added, and the mixture was stirredat room temperature for 15 hr. The reaction mixture was diluted withethyl acetate, washed with 1 M hydrochloric acid, then with saturatedaqueous sodium hydrogen carbonate solution and saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.13 g, 46%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91 (t, J=7.3 Hz, 3H), 1.07 (s, 6H),1.26-1.70 (m, 6H), 2.02-2.44 (m, 4H), 2.84-2.96 (m, 2H), 3.19 (s, 2H),3.35-3.46 (m, 1H), 3.87 (s, 2H), 4.23 (s, 1H), 4.65 (br. s., 1H), 6.42(d, J=2.1 Hz, 1H), 6.73-7.85 (m, 9H)

Example 4404-[trans-4-(2-hydroxypropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one(optically active form, retention time: short)

A mixture of hydroxylammonium chloride (0.69 g), sodium hydrogencarbonate (1.1 g) and dimethyl sulfoxide (4 mL) was stirred at 50° C.for 30 min,4′-({4-[trans-4-(2-hydroxypropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(optically active form, retention time: short, 98.8% ee, 0.42 g) wasadded, and the mixture was stirred at 90° C. for 18 hr. The reactionmixture was diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was dissolved intetrahydrofuran (4 mL). N,N′-Carbonyldiimidazole (0.16 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 mL) were added, and the mixturewas stirred at room temperature for 3 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid, then withsaturated aqueous sodium hydrogen carbonate solution and saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.24 g, 51%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H), 1.04 (d, J=6.4 Hz,3H), 1.23-1.75 (m, 6H), 2.02-2.47 (m, 4H), 2.88-3.47 (m, 5H), 3.59-3.78(m, 1H), 3.93 (s, 2H), 4.52 (d, J=4.7 Hz, 1H), 4.68 (br. s., 1H), 6.41(d, J=2.1 Hz, 1H), 7.18-7.86 (m, 9H), 12.36 (s, 1H)

HPLC (CHIRALPAK AD-H, CO₂/MeOH=750/250, 2.35 mL/min), 2.80 min, 98.8% ee

Example 4414-[trans-4-(2-hydroxypropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one(optically active form, retention time: long)

A mixture of hydroxylammonium chloride (0.69 g), sodium hydrogencarbonate (1.1 g) and dimethyl sulfoxide (4 mL) was stirred at 50° C.for 30 min,4′-({4-[trans-4-(2-hydroxypropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(optically active form, retention time: long, 99.3% ee, 0.42 g) wasadded, and the mixture was stirred at 90° C. for 18 hr. The reactionmixture was diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was dissolved intetrahydrofuran (4 mL). N,N′-Carbonyldiimidazole (0.16 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 mL) were added, and the mixturewas stirred at room temperature for 3 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid, then withsaturated aqueous sodium hydrogen carbonate solution and saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.32 g, 66%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3 Hz, 3H), 1.04 (d, J=6.4 Hz,3H), 1.23-1.75 (m, 6H), 2.02-2.47 (m, 4H), 2.88-3.47 (m, 5H), 3.59-3.78(m, 1H), 3.93 (s, 2H), 4.52 (d, J=4.7 Hz, 1H), 4.68 (br. s., 1H), 6.41(d, J=2.1 Hz, 1H), 7.18-7.86 (m, 9H), 12.36 (s, 1H)

HPLC (CHIRALPAK AD-H, CO₂/MeOH=750/250, 2.35 mL/min), 3.12 min, 93.3% ee

Example 4423-fluoro-4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one

To a solution of ethyl[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-3-fluoro-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate(0.087 g) in tetrahydrofuran (1.5 mL) was added dropwise methylmagnesiumbromide (1 M tetrahydrofuran solution, 0.5 mL) at 0° C., and the mixturewas stirred for 3 hr. To the reaction mixture were added ethyl acetateand then saturated aqueous ammonium chloride solution. The mixture wasextracted with ethyl acetate, and the organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The residue was dissolved in dimethyl sulfoxide (1 mL),hydroxylammonium chloride (0.11 g) and sodium hydrogen carbonate (0.17g) were added and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.042 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.039 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid, then with saturated aqueous sodium hydrogen carbonate solution andsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as apale-yellow amorphous solid (0.037 g, 47%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91 (t, J=7.3 Hz, 3H), 1.06 (s, 6H),1.21-1.54 (m, 4H), 1.72-1.85 (m, 2H), 2.06-2.30 (m, 4H), 2.87-2.98 (m,2H), 3.19 (s, 2H), 3.21-3.28 (m, 1H), 3.93 (s, 2H), 4.23 (s, 1H), 4.75(br. s., 1H), 7.15-8.14 (m, 9H), 12.37 (br. s., 1H)

Example 4437-butyl-4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-6-({6-[2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl]pyridin-3-yl}methyl)pyrazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.35 g), sodium hydrogencarbonate (0.53 g) and dimethyl sulfoxide (2 mL) was stirred at 50° C.for 30 min,2-[5-({7-butyl-4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)pyridin-2-yl]benzonitrile(0.17 g) was added, and the mixture was stirred at 90° C. for 20 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (0.082 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.075 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid, then with saturated aqueous sodium hydrogen carbonate solution andsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.098 g, 53%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.81-0.89 (m, 3H), 1.07 (s, 6H), 1.26-1.73(m, 8H), 2.03-2.45 (m, 4H), 2.96-3.04 (m, 2H), 3.19 (s, 2H), 3.35-3.46(m, 1H), 3.94 (s, 2H), 4.25 (s, 1H), 4.66 (br. s., 1H), 6.42 (d, J=2.3Hz, 1H), 7.53-7.87 (m, 7H), 8.49 (d, J=1.7 Hz, 1H), 12.35 (br. s., 1H)

Example 4446-{[2-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.35 g), sodium hydrogencarbonate (0.53 g) and dimethyl sulfoxide (2 mL) was stirred at 50° C.for 30 min,2′-fluoro-4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.23 g) was added, and the mixture was stirred at 90° C. for 3 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.082 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.075 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, and washed with 1 M hydrochloricacid and then with saturated aqueous sodium hydrogen carbonate solutionand saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless amorphous solid (0.14 g, 56%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H), 1.07 (s, 6H),1.29-1.75 (m, 6H), 2.04-2.43 (m, 4H), 2.91-3.00 (m, 2H), 3.20 (s, 2H),3.36-3.46 (m, 1H), 3.95 (s, 2H), 4.25 (s, 1H), 4.45-4.93 (m, 1H), 6.42(d, J=2.3 Hz, 1H), 7.07-7.87 (m, 8H), 12.59 (s, 1H)

Example 4454-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-6-{[2-methyl-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one

To a solution of4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}-2′-methylbiphenyl-2-carbonitrile(0.88 g) and rhodium acetate (dimer, 0.080 g) in toluene (10 mL) wasadded dropwise ethyl diazoacetate (0.95 mL) at 80° C., and the mixturewas stirred for 3 hr. Ethyl acetate and water were added to the reactionmixture, and the mixture was extracted with ethyl acetate. The organiclayer was washed with water and then with saturated brine, dried overanhydrous magnesium sulfate, and concentrated. The residue was crudelypurified by silica gel column chromatography. This was dissolved intetrahydrofuran (2 mL), methylmagnesium bromide (1.4 M tetrahydrofuransolution, 1.6 mL) was added dropwise thereto at 0° C., and the mixturewas stirred for 2 hr. To the reaction mixture were added ethyl acetateand then saturated aqueous ammonium chloride solution, and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated. This was dissolved in dimethyl sulfoxide (3 mL),hydroxylammonium chloride (0.41 g) and sodium hydrogen carbonate (0.62g) were added, and the mixture was stirred at 90° C. for 20 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (0.096 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.088 mL) were added, andthe mixture was stirred at room temperature for 1 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid, then with saturated aqueous sodium hydrogen carbonate solution andsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as apale-yellow amorphous solid (0.084 g, 28%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91 (t, J=7.2 Hz, 3H), 1.08 (s, 6H),1.26-1.75 (m, 6H), 1.98 (s, 3H), 2.03-2.47 (m, 4H), 2.93 (t, J=7.8 Hz,2H), 3.20 (s, 2H), 3.35-3.46 (m, 1H), 3.89 (s, 2H), 4.25 (s, 1H), 4.67(br. s., 1H), 6.41 (d, J=2.3 Hz, 1H), 6.89-7.85 (m, 8H), 12.39 (s, 1H)

Example 4464-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-6-{1-[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]ethyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one

To a solution of4′-{1-[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]ethyl}biphenyl-2-carbonitrile(0.33 g) and rhodium acetate (dimer, 0.030 g) in toluene (4 mL) wasadded dropwise ethyldiazoacetate (0.36 mL) at 80° C., and the mixturewas stirred for 3 hr. Ethyl acetate and water were added to the reactionmixture, and the mixture was extracted with ethyl acetate. The organiclayer was washed with water and then with saturated brine, dried overanhydrous magnesium sulfate, and concentrated. The residue was crudelypurified by silica gel column chromatography. This was dissolved intetrahydrofuran (2 mL), methylmagnesium bromide (1.4 M tetrahydrofuransolution, 0.62 mL) was added dropwise at 0° C., and the mixture wasstirred for 2 hr. To the reaction mixture were added ethyl acetate andthen saturated aqueous ammonium chloride solution, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated. This was dissolved in dimethyl sulfoxide (1 mL),hydroxylammonium chloride (0.17 g) and sodium hydrogen carbonate (0.25g) were added, and the mixture was stirred at 90° C. for 20 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (1 mL). N,N′-Carbonyldiimidazole (0.036 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.033 mL) were added, andthe mixture was stirred at room temperature for 1 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid, then with saturated aqueous sodium hydrogen carbonate solution andsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as apale-yellow amorphous solid (0.038 g, 34%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91 (t, J=7.2 Hz, 3H), 1.08 (s, 6H),1.26-1.75 (m, 6H), 1.98 (s, 3H), 2.03-2.47 (m, 4H), 2.93 (t, J=7.8 Hz,2H), 3.20 (s, 2H), 3.35-3.46 (m, 1H), 3.89 (s, 2H), 4.25 (s, 1H), 4.67(br. s., 1H), 6.41 (d, J=2.3 Hz, 1H), 6.89-7.85 (m, 8H), 12.39 (s, 1H)

Example 4474-(1,4-dioxaspiro[4.5]dec-8-yl)-6-{[2-nitro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.45 g), sodium hydrogencarbonate (0.68 g) and dimethyl sulfoxide (3 mL) was stirred at 50° C.for 30 min,4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}-2′-nitrobiphenyl-2-carbonitrile(0.30 g) was added, and the mixture was stirred at 90° C. for 3 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (0.105 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.097 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid, then with saturated aqueous sodium hydrogen carbonate solution andsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.15 g, 44%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.3 Hz, 3H), 1.43-1.85 (m, 8H),2.54-2.66 (m, 2H), 2.95-3.07 (m, 2H), 3.85-3.97 (m, 4H), 4.06 (s, 2H),4.80 (br. s., 1H), 6.25 (d, J=1.1 Hz, 1H), 7.26-8.05 (m, 8H), 12.71 (br.s., 1H)

Example 4487-butyl-6-{[2-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]pyrazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.46 g), sodium hydrogencarbonate (0.69 g) and dimethyl sulfoxide (3 mL) was stirred at 50° C.for 30 min,4′-({7-butyl-4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)-2′-fluorobiphenyl-2-carbonitrile(0.31 g) was added, and the mixture was stirred at 90° C. for 15 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (0.14 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.12 mL) were added, andthe mixture was stirred at room temperature for 1 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid, then with saturated aqueous sodium hydrogen carbonate solution andsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as apale-yellow amorphous solid (0.11 g, 44%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.77-0.89 (m, 3H), 1.08 (s, 6H), 1.28-1.52(m, 6H), 1.61-1.75 (m, 2H), 2.03-2.15 (m, 2H), 2.29-2.47 (m, 2H),2.93-3.02 (m, 2H), 3.20 (s, 2H), 3.36-3.48 (m, 1H), 3.95 (s, 2H), 4.24(s, 1H), 4.66 (br. s., 1H), 6.42 (d, J=2.3 Hz, 1H), 7.04-7.88 (m, 8H),12.59 (br. s., 1H)

Example 4494-[4-(1-methylethoxy)phenyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.33 g), sodium hydrogencarbonate (0.50 g) and dimethyl sulfoxide (2 mL) was stirred at 50° C.for 30 min,4′-({4-[4-(1-methylethoxy)phenyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.20 g) was added, and the mixture was stirred at 90° C. for 20 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (0.097 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.090 mL) were added, andthe mixture was stirred at room temperature for 1 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid, then with saturated aqueous sodium hydrogen carbonate solution andsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as apale-yellow amorphous solid (0.15 g, 69%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.96 (t, J=7.2 Hz, 3H), 1.31 (d, J=6.1 Hz,6H), 1.49-1.66 (m, 2H), 2.96-3.06 (m, 2H), 3.98 (s, 2H), 4.60-4.76 (m,1H), 5.44 (d, J=2.3 Hz, 1H), 7.02-7.76 (m, 13H), 12.37 (s, 1H)

Example 4504-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-6-{[3-methoxy-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.64 g), sodium hydrogencarbonate (0.97 g) and dimethyl sulfoxide (5 mL) was stirred at 50° C.for 30 min,4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)-3′-methoxybiphenyl-2-carbonitrile(0.44 g) was added, and the mixture was stirred at 90° C. for 20 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.15 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL) were added, andthe mixture was stirred at room temperature for 1 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid, then with saturated aqueous sodium hydrogen carbonate solution andsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as apale-yellow amorphous solid (0.34 g, 71%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (t, J=7.3 Hz, 3H), 1.07 (s, 6H),1.25-1.75 (m, 6H), 2.02-2.15 (m, 2H), 2.26-2.47 (m, 2H), 2.82-2.94 (m,2H), 3.19 (s, 2H), 3.36-3.46 (m, 1H), 3.76-3.87 (m, 5H), 4.24 (s, 1H),4.65 (br. s., 1H), 6.41 (d, J=2.1 Hz, 1H), 6.75-7.87 (m, 8H), 12.36 (br.s., 1H)

Example 4514-[trans-4-(2-hydroxypropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

To a solution (1 mL) of4-[trans-4-(2-hydroxypropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one(0.10 g) in ethanol was added 8M aqueous potassium hydroxide solution(0.021 mL), and the mixture was stirred at room temperature for 1 hr.The reaction mixture was concentrated under reduced pressure, and theresidue was solidified with diisopropyl ether to give the title compoundas a colorless amorphous solid (0.11 g, 99%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.2 Hz, 3H), 1.04 (d, J=6.1 Hz,3H), 1.23-1.75 (m, 6H), 2.01-2.47 (m, 4H), 2.91-3.01 (m, 2H), 3.17-3.25(m, 1H), 3.33-3.47 (m, 2H), 3.63-3.75 (m, 1H), 3.88 (s, 2H), 4.50 (d,J=4.5 Hz, 1H), 4.68 (br. s., 1H), 6.39 (d, J=1.9 Hz, 1H), 7.09-7.50 (m,8H), 7.81 (d, J=1.9 Hz, 1H).

Example 4524-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-6-{[2-methoxy-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.16 g), sodium hydrogencarbonate (0.25 g) and dimethyl sulfoxide (1 mL) was stirred at 50° C.for 30 min,4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)-2′-methoxybiphenyl-2-carbonitrile(0.085 g) was added, and the mixture was stirred at 90° C. for 20 hr.The reaction mixture was diluted with ethyl acetate, washed with waterand then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was dissolved in tetrahydrofuran (2 mL).N,N′-Carbonyldiimidazole (0.030 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.027 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with 1 M hydrochloric acid, thenwith saturated aqueous sodium hydrogen carbonate solution and saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as apale-yellow amorphous solid (0.058 g, 62%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, 3H), 1.08 (s, 6H), 1.27-1.75 (m,6H), 2.03-2.47 (m, 4H), 2.92-3.02 (m, 2H), 3.34-3.46 (m, 1H), 3.57 (s,3H), 3.94 (s, 2H), 4.24 (s, 1H), 4.66 (br. s., 1H), 6.41 (d, J=2.1 Hz,1H), 6.79-7.87 (m, 8H), 12.36 (s, 1H)

Example 4534-[4-(2-hydroxy-2-methylpropoxy)phenyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.38 g), sodium hydrogencarbonate (0.58 g) and dimethyl sulfoxide (2.5 mL) was stirred at 50° C.for 30 min,4′-({4-[4-(2-hydroxy-2-methylpropoxy)phenyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.25 g) was added, and the mixture was stirred at 90° C. for 15 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (0.090 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.082 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid, then with saturated aqueous sodium hydrogen carbonate solution andsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as apale-yellow amorphous solid (0.19 g, 68%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.96 (t, J=7.4 Hz, 3H), 1.23 (s, 6H),1.50-1.66 (m, 2H), 2.96-3.05 (m, 2H), 3.98 (s, 2H), 4.67 (s, 1H), 5.44(d, J=2.3 Hz, 1H), 7.05-7.76 (m, 13H), 12.37 (s, 1H)

Example 4544-(4-{[(1R,2S)-2-hydroxy-1-methylpropyl]oxy}phenyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.32 g), sodium hydrogencarbonate (0.48 g) and dimethyl sulfoxide (2 mL) was stirred at 50° C.for 30 min,4′-{[4-(4-{[(1R,2S)-2-hydroxy-1-methylpropyl]oxy}phenyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile(0.20 g) was added, and the mixture was stirred at 90° C. for 15 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.062 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.057 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid, then with saturated aqueous sodium hydrogen carbonate solution andsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as apale-yellow amorphous solid (0.11 g, 47%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.96 (t, J=7.4 Hz, 3H), 1.11 (d, J=6.1 Hz,3H), 1.21 (d, J=6.4 Hz, 3H), 1.49-1.66 (m, 2H), 2.96-3.06 (m, 2H),3.73-3.85 (m, 1H), 3.98 (s, 2H), 4.30-4.41 (m, 1H), 4.82 (d, J=4.9 Hz,1H), 5.45 (d, J=1.9 Hz, 1H), 7.05-7.75 (m, 13H), 12.37 (s, 1H)

Example 4554-[4-(2-hydroxypropoxy)phenyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of hydroxylammonium chloride (0.48 g), sodium hydrogencarbonate (0.72 g) and dimethyl sulfoxide (3 mL) was stirred at 50° C.for 30 min,4′-({4-[4-(2-hydroxypropoxy)phenyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile(0.30 g) was added, and the mixture was stirred at 90° C. for 15 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (0.092 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.072 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid, then with saturated aqueous sodium hydrogen carbonate solution andsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as apale-yellow amorphous solid (0.13 g, 38%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.96 (t, J=7.3 Hz, 3H), 1.18 (d, J=6.2 Hz,3H), 1.51-1.65 (m, 2H), 2.95-3.06 (m, 2H), 3.82-4.01 (m, 5H), 4.91 (d,J=4.7 Hz, 1H), 5.43 (d, J=2.1 Hz, 1H), 7.06-7.75 (m, 13H), 12.37 (s, 1H)

Example 4564-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile(0.68 g), {4-[2-(acetyloxy)-1,1-dimethylethoxy]phenyl}boronic acid (0.94g), copper(II) acetate (0.68 g), pyridine (2.0 mL), triethylamine (1.0mL), molecular sieves 4A (2.00 g) and tetrahydrofuran (20 mL) wasstirred at room temperature for 1 day. To the reaction mixture was addedethyl acetate (100 mL), and the mixture was stirred at room temperaturefor 1 hr, and the insoluble material was filtered off. The filtrate wasconcentrated, and the residue was purified by silica gel columnchromatography to give2-(4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}phenoxy)-2-methylpropylacetate as a colorless oil (0.85 g, 80%). A mixture of hydroxylammoniumchloride (1.55 g), sodium hydrogen carbonate (2.50 g) and dimethylsulfoxide (15 mL) was stirred at 40° C. for 30 min,2-(4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}phenoxy)-2-methylpropylacetate (0.85 g) was added, and the mixture was stirred at 90° C. for 18hr. The reaction mixture was diluted with ethyl acetate, washed withwater and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was dissolved in tetrahydrofuran (15 mL).N,N′-Carbonyldiimidazole (0.36 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.33 mL) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogensulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.25 g,28%).

¹H NMR (300 MHz, CDCl₃) δ 1.14 (t, J=7.5 Hz, 3H), 1.33 (s, 6H),1.78-1.96 (m, 2H), 2.21 (br. s, 1H), 3.10-3.24 (m, 2H), 3.59 (s, 2H),4.02 (s, 2H), 7.06-7.16 (m, 2H), 7.18-7.52 (m, 8H), 7.56-7.63 (m, 1H),7.77-7.84 (m, 1H), 7.86 (s, 1H)

Example 4577-butyl-6-{[3-fluoro-2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl][1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one

A mixture of4′-({7-butyl-4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)-3′-fluorobiphenyl-2-carbonitrile(0.76 g), dibutyltin oxide (0.17 g), azidotrimethylsilane (4.60 g) andtoluene (15 mL) was refluxed overnight. The reaction mixture was dilutedwith ethyl acetate, washed with water and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. To a solution of the residue in tetrahydrofuran (15mL) was added tetrabutylammonium fluoride (1.0 M tetrahydrofuransolution, 3 mL) at room temperature, and the mixture was refluxed for 3hr. The reaction mixture was poured into 1 M hydrochloric acid, and themixture was extracted with ethyl acetate. The obtained ethyl acetatelayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The obtained residue was purified by silica gel column chromatography togive the title compound as a colorless amorphous solid (0.58 g, 71%).

¹H NMR (300 MHz, CDCl₃) δ 0.96 (t, J=7.2 Hz, 3H), 1.19 (s, 6H),1.34-1.84 (m, 8H), 2.12-2.24 (m, 2H), 2.39 (br. s, 1H), 2.58-2.76 (m,2H), 3.04-3.12 (m, 2H), 3.29 (s, 2H), 3.34-3.50 (m, 1H), 3.97 (s, 2H),4.96-5.10 (m, 1H), 6.84-6.99 (m, 2H), 7.22-7.30 (m, 1H), 7.37-7.42 (m,1H), 7.50-7.62 (m, 2H), 7.91 (s, 1H), 8.07-8.13 (m, 1H)

Example 458

(+)-6-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one,and(+)-6-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onemonopotassium salt (1/1) hydrate

A solution of(+)-6-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(retention time: short, 107 g) and potassium 2-ethylhexanoate (28.9 g)in ethanol (214 mL) was heated to 60° C., and heptane (1066 mL) wasadded. The reaction mixture was stirred at 60° C. for 16 hr, and theobtained crystals were collected by filtration and washed withdiisopropyl ether (89.6 g, 80%).

(+)-6-{[3-Fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-oneand(+)-6-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidine-5(4H)-onemonopotassium salt (1/1) hydrate (94.9 g) obtained by theabove-mentioned method was suspended in ethanol (475 mL) and dissolvedby heating to 65° C. Heptane (1423 mL) was added at internal temperature60° C., a seed crystal was added, and the mixture was stirred at thesame temperature for 3 hr. At the same temperature, moreover, heptane(475 mL) was added, and the mixture was stirred at the same temperaturefor 1 hr and then at room temperature for 30 min. The obtained crystalswere collected by filtration, and washed with heptane:ethanol (4:1)(86.2 g, 91%, >99% ee).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90-1.10 (m, 12H), 1.16-1.40 (m, 2H),1.49-1.74 (m, 4H), 1.93-2.15 (m, 2H), 2.47-2.68 (m, 2H), 2.87-3.01 (m,2H), 3.25 (q, J=6.2 Hz, 1H), 3.30-3.44 (m, 1H), 3.92 (s, 2H), 4.79-4.95(m, 1H), 7.00 (dd, J=8.0, 1.6 Hz, 1H), 7.08-7.23 (m, 2H), 7.38-7.63 (m,4 H), 8.19 (s, 1H)

Analysis of Enantiomeric Excess

column: CHIRALPAK AD-H (LA145) 4.6 mm ID×250 mL

mobile phase: CO₂/MeOH=650/350 (v/v)

flow rate: 2.35 ml/min

pressure: 100 bar

temperature: 35° C.

detection: UV220 nm

concentration: 0.5 mg/ml

injection volume: 5 μl

retention time: 7.3 min

specific optical rotation [α]²⁵ _(D)+14.6° (c=1.0490, in methanol)

Anal. Calcd for C₆₈H₇₇N₁₂O₁₀F₂KH₂O: C, 61.99; H, 6.04; N, 12.76. Found:C, 62.03; H, 6.07; N, 12.69.

Crystal form was characterized by powder X ray diffraction pattern usingCuKα X-ray radiation, having peaks selected from a list consisting of:

diffraction angle: 2θ (°) interplanar distance: d value (Å) 4.66 18.94685.8 15.2251 6.52 13.5453 9.34 9.461 12.14 7.2844 13.08 6.763 13.16 6.72215.8 5.6043 19.64 4.5164 19.7 4.5027

Example 459(−)-6-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt (retention time: long)

To a solution (30 mL) of6-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(retention time: long, 3 g) in isopropyl alcohol was added 4N aqueouspotassium hydroxide solution (1.2 mL) at room temperature. The reactionmixture was concentrated under reduced pressure, the obtained solid wassuspended in diisopropyl ether, and the mixture was stirred for 1 day.The obtained solid was collected by filtration and washed withdiisopropyl ether to give the title compound (2.8 g, 88%, >99.9% ee).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90-1.11 (m, 15H), 1.17-1.39 (m, 2H),1.54-1.74 (m, 4H), 1.94-2.14 (m, 2H), 2.52-2.65 (m, 2H), 2.90-2.99 (m,2H), 3.24 (q, J=6.4 Hz, 1H), 3.34-3.43 (m, 1H), 3.90 (s, 2H), 4.05 (s,1H), 4.80-4.96 (m, 1H), 6.97-7.17 (m, 3H), 7.28-7.53 (m, 4H), 8.18 (s,1H)

Analysis of Enantiomeric Excess

column: CHIRALPAK AD-H (CG075) 4.6 mm ID×250 mL

mobile phase: CO₂/MeOH=650/350 (v/v)

flow rate: 2.35 ml/min

temperature: 35° C.

detection: UV220 nm

concentration: 0.5 mg/ml

injection volume: 5 μl

retention time: 9.7 min

specific optical rotation [α]²⁵ _(D)−13.6° (c=0.4205, in methanol)

Example 460(−)-6-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-oneand(−)-6-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onemonopotassium salt (1/1) hydrate

A solution (0.64 mL) of6-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one(retention time: long, 0.32 mg) and potassium 2-ethylhexanoate (86 mg)in ethanol was heated to 60° C., and heptane (1.9 mL) was added. Thereaction mixture was stirred at 60° C. for 1 hr, heptane (1.3 mL) wasadded, and the mixture was further stirred at 60° C. for 1 hr. Thereaction mixture was cooled to room temperature, and the obtainedcrystals were collected by filtration and washed with diisopropyl ether(249 mg, 74%).

(−)-6-{[3-Fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-oneand(−)-6-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onemonopotassium salt (1/1) hydrate (249 mg) obtained by theabove-mentioned method was suspended in ethanol (1.75 mL), and dissolvedby heating to 60° C. Heptane (5.25 mL) was added at internal temperature60° C., a seed crystal was added, and the mixture was stirred at thesame temperature for 3 hr. At the same temperature, moreover, heptane(1.75 mL) was added, and the mixture was stirred at the same temperaturefor 1 hr and then at room temperature for 30 min. The obtained crystalswere collected by filtration, and washed with heptane:ethanol (4:1) (211mg, 85%, >99.0% ee).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89-1.11 (m, 12H), 1.18-1.38 (m, 2H),1.51-1.73 (m, 4H), 1.94-2.14 (m, 2H), 2.51-2.66 (m, 2H), 2.88-2.98 (m,2H), 3.24 (q, J=6.0 Hz, 1H), 3.29-3.43 (m, 1H), 3.92 (s, 2H), 4.06 (br.s., 1H), 4.79-4.95 (m, 1H), 7.00 (dd, J=7.9, 1.5 Hz, 1H), 7.08-7.23 (m,2H), 7.39-7.63 (m, 4H), 8.18 (s, 1H)

Analysis of Enantiomeric Excess

column: CHIRALPAK AD-H (LA145) 4.6 mm ID×250 mL

mobile phase: CO₂/MeOH=650/350 (v/v)

flow rate: 2.35 ml/min

pressure: 100 bar

temperature: 35° C.

detection: UV220 nm

concentration: 1.0 mg/ml

injection volume: 5 μl

retention time: 10.9 min

specific optical rotation [α]²⁵ _(D)−13.0° (c=0.4985, in methanol)

Anal. Calcd for C₆₈H₇₇N₁₂O₁₀F₂KH₂O: C, 61.99; H, 6.04; N, 12.76. Found:C, 62.21; H, 5.94; N, 12.83.

Example 4614-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one

4-[trans-4-(2-Hydroxy-2-methylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one(5.0 g) obtained in Example 413 was dissolved in 90% acetone water (40mL) prepared in advance at 25-30° C., water (8 mL) was added, then aseed crystal (25 mg) was added and the mixture was stirred overnight at20-30° C. After stirring, water (24 mL) was added dropwise at 20-30° C.for 4 hr and 10 min. After the completion of the dropwise addition, themixture was stirred at the same temperature for 2 hr and 30 min. Afterstirring, the crystals were collected by filtration and washed with 50%acetone/water (15 mL) prepared in advance to give wet crystals. Theobtained wet crystals were dried under reduced pressure at 40° C. togive the title compound as a crystalline powder (4.72 g, 94.4%).

The title compound was also obtained by the following method.

4-[trans-4-(2-Hydroxy-2-methylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one(3.0 g) obtained in Example 413 was suspended in acetone (39 mL), andthe suspension was dissolved by heating to 45-50° C. and n-heptane (39mL) was further added. After the addition, the mixture was cooled to25-35° C., a seed crystal (15 mg) was added, and the mixture was stirredat 20-30° C. overnight. After stirring, the crystals were collected byfiltration and washed with acetone/n-heptane (1:1, 9 mL) prepared inadvance to give wet crystals. The obtained wet crystals were dried underreduced pressure at 40° C. to give the title compound as a crystallinepowder (1.83 g, yield: 61.0%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3 Hz, 3H), 1.08 (s, 6H), 1.36(dd, J=9.1, 12.6 Hz, 2H), 1.52 (dd, J=7.6, 7.9 Hz, 2H), 1.68 (d, J=9.3Hz, 2H), 2.10 (d, J=7.2 Hz, 2H), 2.39 (m, 2H), 2.96 (t, J=12.8 Hz, 2H),3.21 (s, 2H), 3.40 (m, 1H), 3.94 (s, 2H), 4.25 (s, 1H), 6.42 (s, 1H),7.23 (d, J=8.2 Hz, 2H), 7.30 (d, J=8.2 Hz, 2H), 7.51 (d, J=7.9 Hz, 1H),7.55 (dd, J=7.6, 7.6 Hz, 1H), 7.66 (d, J=7.5 Hz, 1H), 7.69 (dd, J=7.5,7.5 Hz, 1H), 7.83 (d, J=2.2 Hz, 1H), 12.36 (s, 1H)

Crystal form was characterized by powder X ray diffraction pattern usingCuKα X-ray radiation, having peaks selected from a list consisting of:

diffraction angle: 2θ (°) interplanar distance: d value (Å) 9.66 9.14839.92 8.9091 10.68 8.2767 15.82 5.5973 16.32 5.4269 17.22 5.1452 19.024.6622 19.36 4.581 19.78 4.4847 20.02 4.4315 20.68 4.2915 23.54 3.7762

Example 4624-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

4-[trans-4-(2-Hydroxy-2-methylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one(1.16 g) was dissolved in acetonitrile (5 mL), and 8 M aqueous potassiumhydroxide solution (242 μL) was added at 40° C. The reaction mixture wascooled to room temperature. After confirmation of crystal precipitation,the reaction mixture was further stirred at 5° C. for 1 hr. The obtainedcrystals were collected by filtration, and washed with acetonitrile(0.83 g, 67%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.3 Hz, 3H), 1.08 (s, 6H),1.27-1.42 (m, 2H), 1.57 (dq, J=15.1, 7.5 Hz, 2H), 1.68 (d, J=10.7 Hz,2H), 2.09 (d, J=10.4 Hz, 2H), 2.38 (d, J=12.0 Hz, 2H), 2.92-3.01 (m,2H), 3.20 (s, 2H), 3.28-3.44 (m, 1H), 3.89 (s, 2H), 4.25 (br. s., 1H),4.49-4.88 (m, 1H), 6.40 (d, J=2.2 Hz, 1H), 7.12-7.18 (m, 2H), 7.18-7.24(m, 2H), 7.28 (d, J=7.6 Hz, 1H), 7.31-7.37 (m, 1H), 7.38-7.44 (m, 1H),7.48 (d, J=7.3 Hz, 1H), 7.81 (d, J=1.9 Hz, 1H)

Crystal form was characterized by powder X ray diffraction pattern usingCuKα X-ray radiation, having peaks selected from a list consisting of:

diffraction angle: 2θ (°) interplanar distance: d value (Å) 14.98 5.909215.02 5.8935 15.08 5.8702 16.6 5.336 16.68 5.3106 18.78 4.7212 18.864.7014 19.34 4.5857 19.42 4.567 21.32 4.1641

Example 463

4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

4-[trans-4-(2-Hydroxy-2-methylpropoxy)cyclohexyl]-6-[([2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt (0.1 g) was dissolved in ethyl acetate (1 mL) at 50° C.,and the solution was cooled to room temperature. Heptane (0.5 mL) wasadded, and the mixture was stirred under ice-cooling for 1 hr. Theobtained crystals were collected by filtration, and washed with heptane(0.085 g, 85%.

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.3 Hz, 3H), 1.08 (s, 6H),1.27-1.42 (m, 2H), 1.57 (dq, J=15.1, 7.5 Hz, 2H), 1.68 (d, J=10.7 Hz,2H), 2.09 (d, J=10.4 Hz, 2H), 2.38 (d, J=12.0 Hz, 2H), 2.92-3.01 (m,2H), 3.20 (s, 2H), 3.28-3.44 (m, 1H), 3.89 (s, 2H), 4.25 (br. s., 1H),4.49-4.88 (m, 1H), 6.40 (d, J=2.2 Hz, 1H), 7.12-7.18 (m, 2H), 7.18-7.24(m, 2H), 7.28 (d, J=7.6 Hz, 1H), 7.31-7.37 (m, 1H), 7.38-7.44 (m, 1H),7.48 (d, J=7.3 Hz, 1H), 7.81 (d, J=1.9 Hz, 1H)

Crystal form was characterized by powder X ray diffraction pattern usingCuKα X-ray radiation, having peaks selected from a list consisting of:

diffraction angle: 2θ (°) interplanar distance: d value (Å) 4.36 20.24988.8 10.0403 15.06 5.878 16.62 5.3296 17.68 5.0124 18.82 4.7113 19.344.5857 21.36 4.1564 22.02 4.0333 22.32 3.9798

Example 4644-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt

To4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one(10 g) were added ethanol (30 mL) and 8 M potassium hydroxide (2.1 ml),and the mixture was dissolved by stirring at room temperature. After themixture was concentrated, ethyl acetate (50 mL) was added to the residueand the mixture was concentrated again. Ethyl acetate (30 mL) was addedto dissolve the concentrated residue and insoluble material was removedby filtration using ethyl acetate (20 mL). After heating to 60° C., aseed crystal was added to allow crystallization. After crystallization,n-heptane (25 mL) was added dropwise at 60° C., and the mixture wasstirred at the same temperature for about 1 hr, allowed to cool to roomtemperature, and stirred for about 15 hr. The crystals were collected byfiltration and washed with ethyl acetate/n-heptane (1:4, 30 mL) anddried under reduced pressure at 40° C. to give the title compound as acolorless amorphous solid (9.5 g, 89%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.3 Hz, 3H), 1.08 (s, 6H),1.27-1.42 (m, 2H), 1.57 (dq, J=15.1, 7.5 Hz, 2H), 1.68 (d, J=10.7 Hz,2H), 2.09 (d, J=10.4 Hz, 2H), 2.38 (d, J=12.0 Hz, 2H), 2.92-3.01 (m,2H), 3.20 (s, 2H), 3.28-3.44 (m, 1H), 3.89 (s, 2H), 4.25 (br. s., 1H),4.49-4.88 (m, 1H), 6.40 (d, J=2.2 Hz, 1H), 7.12-7.18 (m, 2H), 7.18-7.24(m, 2H), 7.28 (d, J=7.6 Hz, 1H), 7.31-7.37 (m, 1H), 7.38-7.44 (m, 1H),7.48 (d, J=7.3 Hz, 1H), 7.81 (d, J=1.9 Hz, 1 H)

Crystal form was characterized by powder X ray diffraction pattern usingCuKα X-ray radiation, having peaks selected from a list consisting of:

diffraction angle: 2θ (°) interplanar distance: d value (Å) 5.34 16.53557.36 12.0011 7.82 11.2962 11.74 7.5317 12.34 7.1668 16.2 5.4668 18.984.6719 19.78 4.4847 24.78 3.59

Experimental Example 1 Evaluation of AT1 Receptor Antagonistic Activity

(1) Preparation of Human AT1 Receptor-Expressing CHO-K1 CellularMembrane Fraction

CHO-K1 cell (RIKEN, Japan) capable of stable expression of human AT1receptor was cultured, recovered, suspended in homogenize buffer (10 mMNaHCO₃ (pH 7.4), 5 mM EDTA, 1× Complete EDTA free) [manufactured byRoche, Switzerland], and homogenized. The homogenate was centrifuged atlow-speed (900×g, 10 min, 4° C.), and the supernatant was recovered andultracentrifuged (90,000×g, 1 hr, 4° C.). The supernatant was discarded,and the pellets were resuspended in suspension buffer (50 mM Tris (pH7.4), 1 mM EDTA, 1× Complete EDTA free).

(2) Evaluation of AT1 Receptor Antagonistic Activity

The binding assay was performed using 22.5 pM [¹²⁵I]-angiotensin II[manufactured by PerkinElmer, USA] (9 μg) in the presence of AT1membrane and test compound in 100 μl, (total reaction volume) ofreaction buffer (50 mM Tris (pH 7.4), 10 mM MgCl₂ supplemented or notsupplemented with 0.3 mg/mL fatty acid-free bovine serum albumin[manufactured by Wako Pure Chemical Industries, Ltd., Japan]). Thereaction mixture was incubated in 96 well polypropylene plate for 1 hrat room temperature, and the reaction was quenched by rapid filtration(96 well cell harvester) through a GF/C filter treated with wash buffer(50 mM Tris (pH 7.4)). Subsequently, the filter was washed 5 times with0.3 mL of ice-cooled wash buffer. The filter was air-dried, and[¹²⁵I]-angiotensin II binding radioactivity was assayed with Top Countscintillation counter. Total binding was measured in the presence of 1%DMSO and nonspecific binding was measured in the presence of 1Candesartan. The binding data B/B0(%) was analyzed by GraphPad Prismprogram (GraphPad Software Inc.) and the IC₅₀ value (compoundconcentration showing 50% of the maximum value of inhibition percent) ofthe test compound was calculated.

The AT1 receptor binding ratio of [¹²⁵I]-angiotensin II (hereinafter tobe abbreviated as [¹²⁵I]-AII in the formula) (B/B0(%)) was calculatedfrom the following formula.

${{B/B}\; 0\mspace{14mu}(\%)} = {\frac{\begin{pmatrix}{\left\lbrack {}^{125}I \right\rbrack\mspace{14mu} A\; I\; I\mspace{14mu}{binding}\mspace{14mu}{level}\mspace{14mu}{in}\mspace{14mu}{the}\mspace{14mu}{presence}\mspace{14mu}{of}} \\{{{test}\mspace{14mu}{compound}} - {{non}\text{-}{specific}\mspace{14mu}{binding}\mspace{14mu}{level}}}\end{pmatrix}}{\begin{pmatrix}{\left\lbrack {}^{125}I \right\rbrack\mspace{14mu} A\; I\; I\mspace{14mu}{total}\mspace{14mu}{binding}\mspace{14mu}{level}\mspace{14mu}{in}\mspace{14mu}{the}\mspace{14mu}{absence}} \\{{{of}\mspace{14mu}{test}\mspace{14mu}{compound}} - {{non}\text{-}{specific}\mspace{14mu}{binding}\mspace{14mu}{level}}}\end{pmatrix}} \times 100}$

The non-specific binding level is the [¹²⁵I]-angiotensin II bindinglevel obtained in the presence of 1 μM cold angiotensin II.

The results are shown in Tables 1 to 5.

Experimental Example 2 Evaluation of PPARγ Agonistic Activity

(1) Cloning of Human PPARγ Gene

Human PPARγ gene was cloned by a PCR method using heart cDNA[manufactured by Toyobo Co., Ltd., QUICK-Clone cDNA] as a template, anda primer set shown below which was prepared by reference to the basesequence of PPARγ gene reported by Greene et al. [Gene Expr., 1995, vol.4(4-5), pp. 281-299].

(SEQ ID NO: 1) PAG-U: 5′-GTG GGT ACC GAA ATG ACC ATG GTT GAC ACA GAG-3′(SEQ ID NO: 2) PAG-L: 5′-GGG GTC GAC CAG GAC TCT CTG CTA GTA CAA GTC-3′

PCR reaction was performed according to Hot Start method using AmpliWaxPCR Gem 100 [manufactured by Takara Shuzo Co., Ltd., Japan]. First,10×LA PCR Buffer (2 μl), 2.5 mM dNTP solution (3 μl), 12.5 μM primersolution (each 2.5 μl) and sterile distilled water (10 μl) were mixed togive a bottom layer solution mixture. In addition, human heart cDNA (1ng/ml, 1 μl) as a template, 10×LA PCR Buffer (3 μl), 2.5 mM dNTPsolution (1 μl), TaKaRa LA Taq DNA polymerase [manufactured by TakaraShuzo Co., Ltd., Japan] (0.5 μl) and sterile distilled water (24.5 μl)were mixed to give a top layer solution mixture.

To the bottom layer solution mixture described above was added one unitof AmpliWax PCR Gem 100 [manufactured by Takara Shuzo Co., Ltd., Japan],which was treated at 70° C. for 5 minutes and then in ice for 5 minutes.Then, the top layer solution mixture was added to the mixture to preparethe reaction mixture for PCR. A tube comprising the reaction mixture wasset on a thermal cycler [manufactured by PerkinElmer, USA] and treatedat 95° C. for 2 minutes. Furthermore, after repeating the cycle of 95°C. for 15 seconds and 68° C. for 2 minutes 35 times, the tube wastreated at 72° C. for 8 minutes.

The PCR product thus obtained was subjected to electrophoresis onagarose gel (1%), and 1.4 kb DNA fragment comprising PPARγ gene wasrecovered from the gel, and then inserted into pT7 Blue-T vector[manufactured by Takara Shuzo Co., Ltd., Japan] to obtain plasmidpTBT-hPPARγ.

(2) Cloning of Human RXRα Gene

A human RXRα gene was cloned by a PCR method using kidney cDNA[manufactured by Toyobo Co., Ltd., QUICK-Clone cDNA] as a template, anda primer set shown below which was prepared with reference to the basesequence of RXRα gene reported by Mangelsdorf, D. J. et al. (Nature,1990, vol. 345 (6272), pp. 224-229).

(SEQ ID NO: 3) XRA-U: 5′-TTA GAA TTC GAC ATG GAC ACC AAA CAT TTC CTG-3′(SEQ ID NO: 4) XRA-L: 5′-CCC CTC GAG CTA AGT CAT TTG GTG CGG CGC CTC-3′

PCR reaction was performed according to Hot Start method using AmpliWaxPCR Gem 100 [manufactured by Takara Shuzo Co., Ltd., Japan]. First,10×LA PCR Buffer (2 μl), 2.5 mM dNTP solution (3 μl), 12.5 μM primersolution (each 2.5 μl) and sterile distilled water (10 μl) were mixed togive a bottom layer solution mixture. In addition, human kidney cDNA (1ng/ml, 1 μl) as a template, 10×LA PCR Buffer (3 μl), 2.5 mM dNTPsolution (1 μl), TaKaRα LA Taq DNA polymerase [manufactured by TakaraShuzo Co., Ltd., Japan] (0.5 μl) and sterile distilled water (24.5 μl)were mixed to give a top layer solution mixture.

To the bottom layer solution mixture described above was added one unitof AmpliWax PCR Gem 100 [manufactured by Takara Shuzo Co., Ltd., Japan],which was treated at 70° C. for 5 minutes and then in ice for 5 minutes.Then, the top layer solution mixture was added to the mixture to preparethe reaction mixture for PCR. A tube comprising the reaction mixture wasset on a thermal cycler [manufactured by PerkinElmer, USA] and treatedat 95° C. for 2 minutes. Furthermore, after repeating the cycle of 95°C. for 15 seconds and 68° C. for 2 minutes 35 times, the tube wastreated at 72° C. for 8 minutes.

The PCR product thus obtained was subjected to electrophoresis onagarose gel (1%), and 1.4 kb DNA fragment comprising RXRα gene wasrecovered from the gel, and then inserted into pT7 Blue-T vector[manufactured by Takara Shuzo Co., Ltd., Japan] to obtain plasmidpTBT-hRXRα.

(3) Construction of Reporter Plasmid

A DNA fragment comprising PPAR-response element (PPRE) of an acyl CoAoxidase was prepared using the following 5′-terminal phosphorylatedsynthetic DNA.

(SEQ ID NO: 5) PPRE-U: 5′-pTCGACAGGGGACCAGGACAAAGGTCACGTTCGGGAG- 3′ (SEQID NO: 6) PPRE-L: 5′-pTCGACTCCCGAACGTGACCTTTGTCCTGGTCCCCTG- 3′

First, PPRE-U and PPRE-L were annealed and inserted to SalI site ofplasmid pBlueScript SK+. By determining the base sequence of theinserted fragment, plasmid pBSS-PPRE4, in which 4 PPREs were ligated intandem, was selected.

An HSV thymidine kinase minimum promoter (TK promoter) region was clonedby a PCR method using pRL-TK vector [manufactured by Promega, USA] as atemplate, and a primer set shown below which was prepared with referenceto the base sequence of the promoter region of thymidine kinase genereported by Luckow, B et al. (Nucleic Acids Res., 1987, vol. 15(13), p.5490).

(SEQ ID NO: 7) TK-U: 5′-CCCAGATCTCCCCAGCGTCTTGTCATTG-3′ (SEQ ID NO: 8)TK-L: 5′-TCACCATGGTCAAGCTTTTAAGCGGGTC-3′

PCR reaction was performed according to Hot Start method using AmpliWaxPCR Gem 100 [manufactured by Takara Shuzo Co., Ltd., Japan]. First,10×LA PCR Buffer (2 μl), 2.5 mM dNTP solution (3 μl), 12.5 μM primersolution (each 2.5 μl) and sterile distilled water (10 μl) were mixed togive a bottom layer solution mixture. In addition, pRL-TK vector[manufactured by Promega, USA] (1 μl) as a template, 10×LA PCR Buffer (3μl), 2.5 mM dNTP solution (1 μl), TaKaRa LA Taq DNA polymerase[manufactured by Takara Shuzo Co., Ltd., Japan] (0.5 μl) and steriledistilled water (24.5 μl) were mixed to give a top layer solutionmixture.

To the bottom layer solution mixture described above was added one unitof AmpliWax PCR Gem 100 [manufactured by Takara Shuzo Co., Ltd., Japan],which was treated at 70° C. for 5 minutes and then in ice for 5 minutes.Then, the top layer solution mixture was added to the mixture to preparethe reaction mixture for PCR. A tube comprising the reaction mixture wasset on a thermal cycler [manufactured by PerkinElmer, USA] and treatedat 95° C. for 2 minutes.

Furthermore, after repeating the cycle of 95° C. for 15 seconds and 68°C. for 2 minutes 35 times, the tube was treated at 72° C. for 8 minutes.

The PCR product thus obtained was subjected to electrophoresis onagarose gel (1%), and 140 bp DNA fragment comprising TK promoter wasrecovered from the gel, and then inserted into pT7 Blue-T vector[manufactured by Takara Shuzo Co., Ltd., Japan]. By digesting theplasmid thus obtained with the restriction enzymes BglII and NcoI, afragment comprising TK promoter was obtained, which was ligated to theBglII-NcoI fragment of plasmid pGL3-Basic vector [manufactured byPromega, USA] to obtain plasmid pGL3-TK.

A 4.9 kb NheI-XhoI fragment of plasmid pGL3-TK thus obtained was ligatedto a 200 bp NheI-XhoI fragment of plasmid pBSS-PPRE4 to obtain plasmidpGL3-4ERPP-TK.

This plasmid pGL3-4ERPP-TK was digested with BamHI [manufactured byTakara Shuzo Co., Ltd., Japan], and then treated with T4DNA polymerase[manufactured by Takara Shuzo Co., Ltd., Japan] to form a blunt-end,whereby obtaining a DNA fragment.

On the other hand, pGFP-C1 [manufactured by Toyobo Co., Ltd., Japan] wasdigested with Bsu36I (manufactured by NEB, UK], and then treated withT4DNA polymerase [manufactured by Takara Shuzo Co., Ltd., Japan] to forma blunt-end, whereby obtaining a 1.6 kb DNA fragment.

The both DNA fragments were ligated to construct a reporter plasmidpGL3-4ERPP-TK neo.

(4) Construction of Expression Plasmid for Human PPARγ and RXRα

A 7.8 kb FspI-NotI fragment of plasmid pVgRXR [manufactured byInvitrogen, USA] was ligated to a 0.9 kb FspI-NotI fragment comprisingRXRα gene of plasmid pTBT-hRXRα obtained in the above-mentioned (2) toprepare plasmid pVgRXR2. Then, pVgRXR2 was digested with BstXI, and thentreated with T4DNA polymerase [manufactured by Takara Shuzo Co., Ltd.,Japan] to give a blunt-ended product. Then digestion with KpnI gave a6.5 kb DNA fragment.

On the other hand, plasmid pTBT-hPPARγ obtained in the above-mentioned(1) was digested with SalI, and then treated with T4DNA polymerase[manufactured by Takara Shuzo Co., Ltd., Japan] to give a blunt-endedproduct. Then digestion with KpnI gave a 1.4 kb DNA fragment comprisinghuman PPARγ gene.

The both DNA fragments were ligated to construct plasmid pVgRXR2-hPPARγ.

(5) Introduction of Human PPARγ- and RXRα-Expression Plasmid andReporter Plasmid into CHO-K1 Cell as Well as Establishment of ExpressedCell

A CHO-K1 cell cultured in a 150 cm² cell culture flask [manufactured byCorning Costar Corporation, USA] comprising Ham's F12 medium[manufactured by INVITROGEN, USA] supplemented with 10% fetal bovineserum [manufactured by INVITROGEN, USA] was taken off by treating with0.5 g/L trypsin-0.2 g/L EDTA (ethylenediamine tetraacetate)[manufactured by Life Technologies, Inc., USA], and then the cell waswashed with PBS (Phosphate-buffered saline) [manufactured by INVITROGEN,USA], centrifuged (1000 rpm, 5 minutes) and suspended in PBS.Subsequently, DNA was introduced into the cell under the conditionsshown below using GENE PULSER [manufactured by Bio-Rad Laboratories,USA].

Namely, to a cuvette having a 0.4 cm gap were added 8×10⁶ cells and 10μg of plasmid pVgRXR2-hPPARγ obtained in the above-mentioned (4) and 10μg of reporter plasmid pGL3-4ERPP-TK neo obtained in the above-mentioned(3), which was subjected to electroporation at the voltage of 0.25 kVunder the capacitance of 960 Subsequently, the cell was transferred intoa F12 medium comprising 10% fetal bovine serum and cultured for 24hours, and then the cell was taken off again and centrifuged. Then, thepellet was suspended in Ham's F12 medium comprising 10% fetal bovineserum supplemented with 500 μg/ml of Geneticin [manufactured byINVITROGEN, USA] and 250 μg/ml of Zeocin [manufactured by INVITROGEN,USA]. The obtained suspension was diluted to the density of 10⁴ cells/mland inoculated in a 96-well plate [manufactured by Corning CostarCorporation, USA], which was cultured in a CO₂ gas incubator at 37° C.,whereby obtaining a Geneticin- and Zeocin-resistant transformant.

Subsequently, after the transformed cell line thus obtained was culturedin a 24-well plate [manufactured by Corning Costar Corporation, USA], acell line in which expression of the luciferase was induced, i.e.,PPARγ:RXRα:4ERPP/CHO-K1 cell was selected by the addition of 10 μMpioglitazone hydrochloride.

(6) Evaluation of PPARγ Agonistic Activity

PPARγ:RXRα:4ERPP/CHO-K1 cells obtained in the above-mentioned (5) werecultured in F12 medium [manufactured by INVITROGEN, USA] containing 10%fetal bovine serum [manufactured by MOREGATE, Australia], seeded in a 96well half-area white plate [manufactured by Corning Coster Corporation,USA] at 5×10³ cells/well, and cultured in a CO₂ incubator at 37° C.overnight.

Then, the medium was removed from the 96 well half-area white plate,hamF12 medium containing 0.1% fatty acid-free bovine serum albumin (BSA)(45 μl) and a test compound (5 μl) were added, and the mixture wascultured in the CO₂ incubator at 37° C. for 1 day. After removing themedium, Picagene 7.5 [manufactured by Dai Nippon Inki, Japan] (20 μl)diluted 2-fold with HBSS (HANKS' BALANCED SALT SOLUTION) [manufacturedby BIO WHITTAKER, USA] was added, and the mixture was stirred. Using1420 ARVO Multilabel Counter [manufactured by PerkinElmer, USA],luciferase activity was measured. The percentage (%) was calculated fromthe luciferase activity of the test compound when the luciferaseactivity of the control compound (compound X:5-[3-(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxyphenyl)propyl]-1,3-oxazolidine-2,4-dione)(1 μM) was taken as 100% and the luciferase activity of the testcompound non-administration group was taken as 0%. The results are shownin Table 1 to Table 5.

TABLE 1 AT1 receptor PPARγ agonistic antagonistic activity activity(activation % Example No. (IC₅₀ (nM)) (10⁻⁶ M)) 2 1.3 18 4 2.6 39 5 1.718 7 2.4 26 9 2.1 17 10 1.8 18 21 2.0 31 28 3.0 49 29 3.0 16 37 2.5 3343 2.1 34 68 1.7 17 69 1.4 27 73 1.5 20 74 2.1 25 78 1.8 21 83 1.5 16107 1.9 16 108 1.5 16 109 2.2 16 113 1.5 20 114 2.0 16 117 1.3 18 1202.0 18 121 1.9 31 124 2.4 21

TABLE 2 AT1 receptor PPARγ agonistic antagonistic activity activity(activation % Example No. (IC₅₀ (nM)) (10⁻⁶ M)) 125 1.9 23 131 2.9 15134 1.3 26 135 0.9 26 136 1.3 17 137 1.4 20 138 1.3 8 139 1.7 6 144 1.420 147 1.0 26 148 1.9 52 150 1.4 58 151 1.6 35 152 2.4 39 153 1.9 53 1542.1 33 155 1.6 18 158 2.5 37 160 1.3 26 161 1.2 47 163 1.6 40 164 1.0 18166 1.3 22 167 0.8 43 168 1.4 54 169 1.4 54 170 1.6 20 173 1.7 28 1791.9 41 180 3.5 31 181 3.2 18 183 2.5 30 184 2.5 41

TABLE 3 AT1 receptor PPARγ agonistic antagonistic activity activity(activation % Example No. (IC₅₀ (nM)) (10⁻⁶ M)) 185 2.3 22 186 2.1 24188 1.9 25 189 3.1 35 191 1.6 34 193 2.0 28 195 2.5 19 197 2.0 17 2042.7 26 205 2.7 27 206 2.2 23 210 1.9 33 215 1.9 24 216 1.6 23 225 2.3 21227 2.5 23 228 1.5 27 232 2.1 35 233 1.9 26 244 2.3 29 247 2.3 17 2482.2 19 249 2.5 35 252 2.4 40 259 2.3 28 269 2.2 16 271 2.4 43 272 2.8 28273 1.7 48

TABLE 4 AT1 receptor PPARγ agonistic antagonistic activity activity(activation % Example No. (IC₅₀ (nM)) (10⁻⁶ M)) 274 2.2 42 275 2.5 31277 2.2 20 278 2.7 22 280 1.9 16 281 1.8 42 282 2.2 53 285 3.1 34 2863.1 39 288 2.7 17 290 3.2 25 292 1.9 46 293 2.3 28 294 2.1 31 296 1.7 29297 2.8 53 299 1.8 19 300 1.8 16 318 1.8 17 319 2.0 16 325 2.0 31 3261.8 29 331 2.0 33 335 1.9 19 337 1.9 24 338 1.6 36 339 1.4 27 345 2.1 18348 1.9 19 352 1.4 20 354 1.2 18 355 1.7 25

TABLE 5 AT1 receptor PPARγ agonistic antagonistic activity activity(activation % Example No. (IC₅₀ (nM)) (10⁻⁶ M)) 360 1.7 19 362 2.5 26363 2.3 22 364 2.8 29 367 2.2 25 368 2.2 19 371 2.1 33 373 3.2 16 3761.2 19 379 2.2 34 381 2.3 32 382 2.9 35 385 2.0 23 391 3.1 28 392 2.2 20403 2.1 17 404 2.7 28 413 1.6 25 419 2.0 21 420 2.2 21 427 1.9 18 4281.9 27 434 2.1 25 435 1.7 30 436 1.8 32 437 1.6 30 440 1.8 16 441 1.6 19442 2.0 22 457 1.8 19

The Example compounds shown in the above Tables are all free forms.

As is clear from the above-mentioned Tables, the compound of the presentinvention showed a superior AT1 receptor antagonistic activity and aPPARγ agonistic activity.

Experimental Example 3

Male SHRs (28-40 weeks old, Japan SLC, Inc., Japan) were anesthetizedwith sodium pentobarbital (50 mg/kg, i.p.). The left femoral artery wascannulated with a polyethylene catheter filled with saline comprisingheparin (200 U/mL). The catheter was exteriorized at the back of theneck and each SHR was individually housed in a cage and left two or fourdays to recover. The mean blood pressure (MBP) was obtained from thesystemic blood pressure which was monitored from the femoral arteryusing a pressure transducer connected to a polygraph system (NihonKohden Corporation). The heart rate was measured from the blood pressurepulse intervals. The rats which had MBP over 150 mmHg were used for theexperiment. When the blood pressure had stabilized, vehicle (0.5 w/v %methylcellulose) or compounds were orally administered. All compoundswere suspended in 0.5 w/v % methylcellulose and orally administered at avolume of 2 mL/kg. The MBP was measured during 24 hours after theadministration. The results are shown in Table 6.

TABLE 6 Example Dose (mg/kg) Maximum MBP reduction (mmHg) 413 10 79 4153 63 458 30 70 459 3 64

As clear from Table 6, the compound of the present invention was shownsuperior antihypertensive effect.

Experimental Example 4

Male 25-31 weeks-old Wistar fatty rats (Takeda Pharmaceutical Company)were divided to each group with equalization of plasma levels oftriglyceride, glucose and body weight in fed condition. The groups ofrats were treated with vehicle (0.5 w/v % methylcellulose) or compounds.All compounds were suspended in 0.5 w/v % methylcellulose and orallyadministered at a volume of 2 mL/kg, once a day for 2 weeks. The nextday of the final administration, blood was collected from the tail veinto measure plasma parameters. Heparin was used as an anticoagulant.Plasma levels of triglyceride and glucose were measured enzymaticallyusing Hitachi Autoanalyser 9000. The inhibition rates from vehicletreatment group were calculated for each compound after the treatmentfor 2 weeks. The results are shown in Table 7.

TABLE 7 Inhibition rate of Dose plasma triglyceride Inhibition rate ofExample (mg/kg) (%) plasma glucose (%) 413 3 12.0 6.5 10 21.5 19.1 3046.0 53.3 415 3 38.1 25.1 10 57.7 54.3 458 3 33.5 −0.2 10 39.0 6.9 3059.2 43.3

As is clear from Table 7, the compound of the present invention showed asuperior plasma glucose and triglyceride lowering effect.

Formulation Examples

Formulation Example 1 (capsule) (1) compound of Example 1 10 mg (2)lactose 90 mg (3) crystalline cellulose 70 mg (4) magnesium stearate 10mg 1 capsule 180 mg 

(1), (2), (3) and ½ of (4) are blended and granulated. The rest of (4)is added and the whole is filled in a gelatin capsule.

Formulation Example 2 (tablet) (1) compound of Example 1 10 mg (2)lactose 35 mg (3) cornstarch 150 mg  (4) crystalline cellulose 30 mg (5)magnesium stearate  5 mg 1 tablet 230 mg 

(1), (2), (3), ⅔ of (4) and ½ of (5) are blended and granulated. Therest of (4) and (5) is added to the granules and the mixture iscompression molded to give tablet.

Formulation Example 3 (injection) (1) compound of Example 1  10 mg (2)inositol 100 mg (3) benzyl alcohol  20 mg 1 ampoule 130 mg

(1), (2) and (3) are dissolved in distilled water for injection to thetotal amount of 2 mL and filled in an ampoule. All steps are performedunder aseptic conditions.

INDUSTRIAL APPLICABILITY

The compound of the present invention has an angiotensin II receptorantagonistic activity and a peroxisome proliferator-activated receptor(PPAR) γ agonistic activity, and is useful as a medicament such as anagent for the prophylaxis or treatment of circulatory diseases such ashypertension, cardiac diseases (cardiac hypertrophy, cardiac failure,myocardial infarction etc.), arteriosclerosis, renal diseases (diabeticnephropathy, chronic glomerulonephritis etc.), ophthalmic diseases,liver diseases, cerebral apoplexy and the like and/or metabolic diseasessuch as hyperlipidemia, obesity, diabetes etc., and the like.

This application is based on Japanese patent application No.2009-020720, the contents of which are incorporated in full herein bythis reference.

1.6-{[3-Fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-oneor a salt thereof.
 2. A medicament comprising effective amount of thecompound according to claim 1 and a pharmaceutically acceptable carrier.3.(+)-6-{[3-Fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-onepotassium salt.
 4. A medicament comprising effective amount of thecompound according to claim 3 and a pharmaceutically acceptable carrier.